Links to Exploration step
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Highlights in Resistance Mechanism Pathways for Combination Therapy</title><author><name sortKey="Delou, Joao M A" sort="Delou, Joao M A" uniqKey="Delou J" first="João M. A." last="Delou">João M. A. Delou</name></author><author><name sortKey="Souza, Alana S O" sort="Souza, Alana S O" uniqKey="Souza A" first="Alana S. O." last="Souza">Alana S. O. Souza</name></author><author><name sortKey="Souza, Leonel C M" sort="Souza, Leonel C M" uniqKey="Souza L" first="Leonel C. M." last="Souza">Leonel C. M. Souza</name></author><author><name sortKey="Borges, Helena L" sort="Borges, Helena L" uniqKey="Borges H" first="Helena L." last="Borges">Helena L. Borges</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31480389</idno><idno type="pmc">6770082</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770082</idno><idno type="RBID">PMC:6770082</idno><idno type="doi">10.3390/cells8091013</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000924</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000924</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Highlights in Resistance Mechanism Pathways for Combination Therapy</title><author><name sortKey="Delou, Joao M A" sort="Delou, Joao M A" uniqKey="Delou J" first="João M. A." last="Delou">João M. A. Delou</name></author><author><name sortKey="Souza, Alana S O" sort="Souza, Alana S O" uniqKey="Souza A" first="Alana S. O." last="Souza">Alana S. O. Souza</name></author><author><name sortKey="Souza, Leonel C M" sort="Souza, Leonel C M" uniqKey="Souza L" first="Leonel C. M." last="Souza">Leonel C. M. Souza</name></author><author><name sortKey="Borges, Helena L" sort="Borges, Helena L" uniqKey="Borges H" first="Helena L." last="Borges">Helena L. Borges</name></author></analytic><series><title level="j">Cells</title><idno type="eISSN">2073-4409</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Combination chemotherapy has been a mainstay in cancer treatment for the last 60 years. Although the mechanisms of action and signaling pathways affected by most treatments with single antineoplastic agents might be relatively well understood, most combinations remain poorly understood. This review presents the most common alterations of signaling pathways in response to cytotoxic and targeted anticancer drug treatments, with a discussion of how the knowledge of signaling pathways might support and orient the development of innovative strategies for anticancer combination therapy. The ultimate goal is to highlight possible strategies of chemotherapy combinations based on the signaling pathways associated with the resistance mechanisms against anticancer drugs to maximize the selective induction of cancer cell death. We consider this review an extensive compilation of updated known information on chemotherapy resistance mechanisms to promote new combination therapies to be to discussed and tested.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Gilman, A" uniqKey="Gilman A">A. Gilman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Devita, V T" uniqKey="Devita V">V.T. DeVita</name></author><author><name sortKey="Chu, E" uniqKey="Chu E">E. Chu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mokhtari, R B" uniqKey="Mokhtari R">R.B. Mokhtari</name></author><author><name sortKey="Homayouni, T S" uniqKey="Homayouni T">T.S. Homayouni</name></author><author><name sortKey="Baluch, N" uniqKey="Baluch N">N. Baluch</name></author><author><name sortKey="Morgatskaya, E" uniqKey="Morgatskaya E">E. Morgatskaya</name></author><author><name sortKey="Kumar, S" uniqKey="Kumar S">S. Kumar</name></author><author><name sortKey="Das, B" uniqKey="Das B">B. Das</name></author><author><name sortKey="Yeger, H" uniqKey="Yeger H">H. Yeger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mansoori, B" uniqKey="Mansoori B">B. Mansoori</name></author><author><name sortKey="Mohammadi, A" uniqKey="Mohammadi A">A. Mohammadi</name></author><author><name sortKey="Davudian, S" uniqKey="Davudian S">S. Davudian</name></author><author><name sortKey="Shirjang, S" uniqKey="Shirjang S">S. Shirjang</name></author><author><name sortKey="Baradaran, B" uniqKey="Baradaran B">B. Baradaran</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goodman, A M" uniqKey="Goodman A">A.M. Goodman</name></author><author><name sortKey="Kato, S" uniqKey="Kato S">S. Kato</name></author><author><name sortKey="Bazhenova, L" uniqKey="Bazhenova L">L. Bazhenova</name></author><author><name sortKey="Patel, S P" uniqKey="Patel S">S.P. Patel</name></author><author><name sortKey="Frampton, G M" uniqKey="Frampton G">G.M. Frampton</name></author><author><name sortKey="Miller, V" uniqKey="Miller V">V. Miller</name></author><author><name sortKey="Stephens, P J" uniqKey="Stephens P">P.J. Stephens</name></author><author><name sortKey="Daniels, G A" uniqKey="Daniels G">G.A. Daniels</name></author><author><name sortKey="Kurzrock, R" uniqKey="Kurzrock R">R. Kurzrock</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jia, Q" uniqKey="Jia Q">Q. Jia</name></author><author><name sortKey="Wu, W" uniqKey="Wu W">W. Wu</name></author><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y. Wang</name></author><author><name sortKey="Alexander, P B" uniqKey="Alexander P">P.B. Alexander</name></author><author><name sortKey="Sun, C" uniqKey="Sun C">C. Sun</name></author><author><name sortKey="Gong, Z" uniqKey="Gong Z">Z. Gong</name></author><author><name sortKey="Cheng, J N" uniqKey="Cheng J">J.-N. Cheng</name></author><author><name sortKey="Sun, H" uniqKey="Sun H">H. Sun</name></author><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y. Guan</name></author><author><name sortKey="Xia, X" uniqKey="Xia X">X. Xia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bruce, W R" uniqKey="Bruce W">W.R. Bruce</name></author><author><name sortKey="Meeker, B E" uniqKey="Meeker B">B.E. Meeker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hill, B T" uniqKey="Hill B">B.T. Hill</name></author><author><name sortKey="Baserga, R" uniqKey="Baserga R">R. Baserga</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Espinosa, E" uniqKey="Espinosa E">E. Espinosa</name></author><author><name sortKey="Zamora, P" uniqKey="Zamora P">P. Zamora</name></author><author><name sortKey="Feliu, J" uniqKey="Feliu J">J. Feliu</name></author><author><name sortKey="Gonzalez Bar N, M" uniqKey="Gonzalez Bar N M">M. González Barón</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, X Z" uniqKey="Wu X">X.-Z. Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dutt, R" uniqKey="Dutt R">R. Dutt</name></author><author><name sortKey="Madan, A K" uniqKey="Madan A">A.K. Madan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pritchard, J R" uniqKey="Pritchard J">J.R. Pritchard</name></author><author><name sortKey="Bruno, P M" uniqKey="Bruno P">P.M. Bruno</name></author><author><name sortKey="Gilbert, L A" uniqKey="Gilbert L">L.A. Gilbert</name></author><author><name sortKey="Capron, K L" uniqKey="Capron K">K.L. Capron</name></author><author><name sortKey="Lauffenburger, D A" uniqKey="Lauffenburger D">D.A. Lauffenburger</name></author><author><name sortKey="Hemann, M T" uniqKey="Hemann M">M.T. Hemann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wishart, D S" uniqKey="Wishart D">D.S. Wishart</name></author><author><name sortKey="Feunang, Y D" uniqKey="Feunang Y">Y.D. Feunang</name></author><author><name sortKey="Guo, A C" uniqKey="Guo A">A.C. Guo</name></author><author><name sortKey="Lo, E J" uniqKey="Lo E">E.J. Lo</name></author><author><name sortKey="Marcu, A" uniqKey="Marcu A">A. Marcu</name></author><author><name sortKey="Grant, J R" uniqKey="Grant J">J.R. Grant</name></author><author><name sortKey="Sajed, T" uniqKey="Sajed T">T. Sajed</name></author><author><name sortKey="Johnson, D" uniqKey="Johnson D">D. Johnson</name></author><author><name sortKey="Li, C" uniqKey="Li C">C. Li</name></author><author><name sortKey="Sayeeda, Z" uniqKey="Sayeeda Z">Z. Sayeeda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Preissner, S" uniqKey="Preissner S">S. Preissner</name></author><author><name sortKey="Kroll, K" uniqKey="Kroll K">K. Kroll</name></author><author><name sortKey="Dunkel, M" uniqKey="Dunkel M">M. Dunkel</name></author><author><name sortKey="Senger, C" uniqKey="Senger C">C. Senger</name></author><author><name sortKey="Goldsobel, G" uniqKey="Goldsobel G">G. Goldsobel</name></author><author><name sortKey="Kuzman, D" uniqKey="Kuzman D">D. Kuzman</name></author><author><name sortKey="Guenther, S" uniqKey="Guenther S">S. Guenther</name></author><author><name sortKey="Winnenburg, R" uniqKey="Winnenburg R">R. Winnenburg</name></author><author><name sortKey="Schroeder, M" uniqKey="Schroeder M">M. Schroeder</name></author><author><name sortKey="Preissner, R" uniqKey="Preissner R">R. Preissner</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Juliano, R L L" uniqKey="Juliano R">R.L.L. Juliano</name></author><author><name sortKey="Ling, V" uniqKey="Ling V">V. Ling</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Robey, R W" uniqKey="Robey R">R.W. Robey</name></author><author><name sortKey="Pluchino, K M" uniqKey="Pluchino K">K.M. Pluchino</name></author><author><name sortKey="Hall, M D" uniqKey="Hall M">M.D. Hall</name></author><author><name sortKey="Fojo, A T" uniqKey="Fojo A">A.T. Fojo</name></author><author><name sortKey="Bates, S E" uniqKey="Bates S">S.E. Bates</name></author><author><name sortKey="Gottesman, M M" uniqKey="Gottesman M">M.M. Gottesman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gottesman, M M" uniqKey="Gottesman M">M.M. Gottesman</name></author><author><name sortKey="Fojo, T" uniqKey="Fojo T">T. Fojo</name></author><author><name sortKey="Bates, S E" uniqKey="Bates S">S.E. Bates</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Szakacs, G" uniqKey="Szakacs G">G. Szakács</name></author><author><name sortKey="Paterson, J K" uniqKey="Paterson J">J.K. Paterson</name></author><author><name sortKey="Ludwig, J A" uniqKey="Ludwig J">J.A. Ludwig</name></author><author><name sortKey="Booth Genthe, C" uniqKey="Booth Genthe C">C. Booth-Genthe</name></author><author><name sortKey="Gottesman, M M" uniqKey="Gottesman M">M.M. Gottesman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Patel, C" uniqKey="Patel C">C. Patel</name></author><author><name sortKey="Stenke, L" uniqKey="Stenke L">L. Stenke</name></author><author><name sortKey="Varma, S" uniqKey="Varma S">S. Varma</name></author><author><name sortKey="Lindberg, M L" uniqKey="Lindberg M">M.L. Lindberg</name></author><author><name sortKey="Bjorkholm, M" uniqKey="Bjorkholm M">M. Björkholm</name></author><author><name sortKey="Sjoberg, J" uniqKey="Sjoberg J">J. Sjöberg</name></author><author><name sortKey="Viktorsson, K" uniqKey="Viktorsson K">K. Viktorsson</name></author><author><name sortKey="Lewensohn, R" uniqKey="Lewensohn R">R. Lewensohn</name></author><author><name sortKey="Landgren, O" uniqKey="Landgren O">O. Landgren</name></author><author><name sortKey="Gottesman, M M" uniqKey="Gottesman M">M.M. Gottesman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bartholomae, S" uniqKey="Bartholomae S">S. Bartholomae</name></author><author><name sortKey="Gruhn, B" uniqKey="Gruhn B">B. Gruhn</name></author><author><name sortKey="Debatin, K M" uniqKey="Debatin K">K.-M. Debatin</name></author><author><name sortKey="Zimmermann, M" uniqKey="Zimmermann M">M. Zimmermann</name></author><author><name sortKey="Creutzig, U" uniqKey="Creutzig U">U. Creutzig</name></author><author><name sortKey="Reinhardt, D" uniqKey="Reinhardt D">D. Reinhardt</name></author><author><name sortKey="Steinbach, D" uniqKey="Steinbach D">D. Steinbach</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marzac, C" uniqKey="Marzac C">C. Marzac</name></author><author><name sortKey="Garrido, E" uniqKey="Garrido E">E. Garrido</name></author><author><name sortKey="Tang, R" uniqKey="Tang R">R. Tang</name></author><author><name sortKey="Fava, F" uniqKey="Fava F">F. Fava</name></author><author><name sortKey="Hirsch, P" uniqKey="Hirsch P">P. Hirsch</name></author><author><name sortKey="De Benedictis, C" uniqKey="De Benedictis C">C. De Benedictis</name></author><author><name sortKey="Corre, E" uniqKey="Corre E">E. Corre</name></author><author><name sortKey="Lapusan, S" uniqKey="Lapusan S">S. Lapusan</name></author><author><name sortKey="Lallemand, J Y" uniqKey="Lallemand J">J.-Y. Lallemand</name></author><author><name sortKey="Marie, J P" uniqKey="Marie J">J.-P. Marie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cui, H" uniqKey="Cui H">H. Cui</name></author><author><name sortKey="Zhang, A" uniqKey="Zhang A">A. Zhang</name></author><author><name sortKey="Chen, M" uniqKey="Chen M">M. Chen</name></author><author><name sortKey="Liu, J" uniqKey="Liu J">J. Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karthikeyan, S" uniqKey="Karthikeyan S">S. Karthikeyan</name></author><author><name sortKey="Hoti, S L" uniqKey="Hoti S">S.L. Hoti</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Zheng, W" uniqKey="Zheng W">W. Zheng</name></author><author><name sortKey="Johnston, S A" uniqKey="Johnston S">S.A. Johnston</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lazo, J S" uniqKey="Lazo J">J.S. Lazo</name></author><author><name sortKey="Boland, C J" uniqKey="Boland C">C.J. Boland</name></author><author><name sortKey="Schwartz, P E" uniqKey="Schwartz P">P.E. Schwartz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lefterov, I M" uniqKey="Lefterov I">I.M. Lefterov</name></author><author><name sortKey="Koldamova, R P" uniqKey="Koldamova R">R.P. Koldamova</name></author><author><name sortKey="King, J" uniqKey="King J">J. King</name></author><author><name sortKey="Lazo, J S" uniqKey="Lazo J">J.S. Lazo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dortet, L" uniqKey="Dortet L">L. Dortet</name></author><author><name sortKey="Girlich, D" uniqKey="Girlich D">D. Girlich</name></author><author><name sortKey="Virlouvet, A L" uniqKey="Virlouvet A">A.-L. Virlouvet</name></author><author><name sortKey="Poirel, L" uniqKey="Poirel L">L. Poirel</name></author><author><name sortKey="Nordmann, P" uniqKey="Nordmann P">P. Nordmann</name></author><author><name sortKey="Iorga, B I" uniqKey="Iorga B">B.I. Iorga</name></author><author><name sortKey="Naas, T" uniqKey="Naas T">T. Naas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ishikawa, T" uniqKey="Ishikawa T">T. Ishikawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Muller, M" uniqKey="Muller M">M. Muller</name></author><author><name sortKey="Meijer, C" uniqKey="Meijer C">C. Meijer</name></author><author><name sortKey="Zaman, G J" uniqKey="Zaman G">G.J. Zaman</name></author><author><name sortKey="Borst, P" uniqKey="Borst P">P. Borst</name></author><author><name sortKey="Scheper, R J" uniqKey="Scheper R">R.J. Scheper</name></author><author><name sortKey="Mulder, N H" uniqKey="Mulder N">N.H. Mulder</name></author><author><name sortKey="De Vries, E G" uniqKey="De Vries E">E.G. de Vries</name></author><author><name sortKey="Jansen, P L" uniqKey="Jansen P">P.L. Jansen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brechbuhl, H M" uniqKey="Brechbuhl H">H.M. Brechbuhl</name></author><author><name sortKey="Gould, N" uniqKey="Gould N">N. Gould</name></author><author><name sortKey="Kachadourian, R" uniqKey="Kachadourian R">R. Kachadourian</name></author><author><name sortKey="Riekhof, W R" uniqKey="Riekhof W">W.R. Riekhof</name></author><author><name sortKey="Voelker, D R" uniqKey="Voelker D">D.R. Voelker</name></author><author><name sortKey="Day, B J" uniqKey="Day B">B.J. Day</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, Y L" uniqKey="Zhang Y">Y.-L. Zhang</name></author><author><name sortKey="Li, B Y" uniqKey="Li B">B.-Y. Li</name></author><author><name sortKey="Yang, R" uniqKey="Yang R">R. Yang</name></author><author><name sortKey="Xia, L Y" uniqKey="Xia L">L.-Y. Xia</name></author><author><name sortKey="Fan, A L" uniqKey="Fan A">A.-L. Fan</name></author><author><name sortKey="Chu, Y C" uniqKey="Chu Y">Y.-C. Chu</name></author><author><name sortKey="Wang, L J" uniqKey="Wang L">L.-J. Wang</name></author><author><name sortKey="Wang, Z C" uniqKey="Wang Z">Z.-C. Wang</name></author><author><name sortKey="Jiang, A Q" uniqKey="Jiang A">A.-Q. Jiang</name></author><author><name sortKey="Zhu, H L" uniqKey="Zhu H">H.-L. Zhu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dumontet, C" uniqKey="Dumontet C">C. Dumontet</name></author><author><name sortKey="Jordan, M A" uniqKey="Jordan M">M.A. Jordan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheung, C H A" uniqKey="Cheung C">C.H.A. Cheung</name></author><author><name sortKey="Wu, S Y" uniqKey="Wu S">S.-Y. Wu</name></author><author><name sortKey="Lee, T R" uniqKey="Lee T">T.-R. Lee</name></author><author><name sortKey="Chang, C Y" uniqKey="Chang C">C.-Y. Chang</name></author><author><name sortKey="Wu, J S" uniqKey="Wu J">J.-S. Wu</name></author><author><name sortKey="Hsieh, H P" uniqKey="Hsieh H">H.-P. Hsieh</name></author><author><name sortKey="Chang, J Y" uniqKey="Chang J">J.-Y. Chang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hari, M" uniqKey="Hari M">M. Hari</name></author><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y. Wang</name></author><author><name sortKey="Veeraraghavan, S" uniqKey="Veeraraghavan S">S. Veeraraghavan</name></author><author><name sortKey="Cabral, F" uniqKey="Cabral F">F. Cabral</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yin, S" uniqKey="Yin S">S. Yin</name></author><author><name sortKey="Bhattacharya, R" uniqKey="Bhattacharya R">R. Bhattacharya</name></author><author><name sortKey="Cabral, F" uniqKey="Cabral F">F. Cabral</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Orr, G A" uniqKey="Orr G">G.A. Orr</name></author><author><name sortKey="Verdier Pinard, P" uniqKey="Verdier Pinard P">P. Verdier-Pinard</name></author><author><name sortKey="Mcdaid, H" uniqKey="Mcdaid H">H. McDaid</name></author><author><name sortKey="Horwitz, S B" uniqKey="Horwitz S">S.B. Horwitz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Binaschi, M" uniqKey="Binaschi M">M. Binaschi</name></author><author><name sortKey="Zunino, F" uniqKey="Zunino F">F. Zunino</name></author><author><name sortKey="Capranico, G" uniqKey="Capranico G">G. Capranico</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hevener, K" uniqKey="Hevener K">K. Hevener</name></author><author><name sortKey="Verstak, T A" uniqKey="Verstak T">T.A. Verstak</name></author><author><name sortKey="Lutat, K E" uniqKey="Lutat K">K.E. Lutat</name></author><author><name sortKey="Riggsbee, D L" uniqKey="Riggsbee D">D.L. Riggsbee</name></author><author><name sortKey="Mooney, J W" uniqKey="Mooney J">J.W. Mooney</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sabini, E" uniqKey="Sabini E">E. Sabini</name></author><author><name sortKey="Hazra, S" uniqKey="Hazra S">S. Hazra</name></author><author><name sortKey="Konrad, M" uniqKey="Konrad M">M. Konrad</name></author><author><name sortKey="Lavie, A" uniqKey="Lavie A">A. Lavie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nathanson, D A" uniqKey="Nathanson D">D.A. Nathanson</name></author><author><name sortKey="Armijo, A L" uniqKey="Armijo A">A.L. Armijo</name></author><author><name sortKey="Tom, M" uniqKey="Tom M">M. Tom</name></author><author><name sortKey="Li, Z" uniqKey="Li Z">Z. Li</name></author><author><name sortKey="Dimitrova, E" uniqKey="Dimitrova E">E. Dimitrova</name></author><author><name sortKey="Austin, W R" uniqKey="Austin W">W.R. Austin</name></author><author><name sortKey="Nomme, J" uniqKey="Nomme J">J. Nomme</name></author><author><name sortKey="Campbell, D O" uniqKey="Campbell D">D.O. Campbell</name></author><author><name sortKey="Ta, L" uniqKey="Ta L">L. Ta</name></author><author><name sortKey="Le, T M" uniqKey="Le T">T.M. Le</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sarkaria, J N" uniqKey="Sarkaria J">J.N. Sarkaria</name></author><author><name sortKey="Kitange, G J" uniqKey="Kitange G">G.J. Kitange</name></author><author><name sortKey="James, C D" uniqKey="James C">C.D. James</name></author><author><name sortKey="Plummer, R" uniqKey="Plummer R">R. Plummer</name></author><author><name sortKey="Calvert, H" uniqKey="Calvert H">H. Calvert</name></author><author><name sortKey="Weller, M" uniqKey="Weller M">M. Weller</name></author><author><name sortKey="Wick, W" uniqKey="Wick W">W. Wick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hegi, M E" uniqKey="Hegi M">M.E. Hegi</name></author><author><name sortKey="Diserens, A C" uniqKey="Diserens A">A.-C. Diserens</name></author><author><name sortKey="Gorlia, T" uniqKey="Gorlia T">T. Gorlia</name></author><author><name sortKey="Hamou, M F" uniqKey="Hamou M">M.-F. Hamou</name></author><author><name sortKey="De Tribolet, N" uniqKey="De Tribolet N">N. de Tribolet</name></author><author><name sortKey="Weller, M" uniqKey="Weller M">M. Weller</name></author><author><name sortKey="Kros, J M" uniqKey="Kros J">J.M. Kros</name></author><author><name sortKey="Hainfellner, J A" uniqKey="Hainfellner J">J.A. Hainfellner</name></author><author><name sortKey="Mason, W" uniqKey="Mason W">W. Mason</name></author><author><name sortKey="Mariani, L" uniqKey="Mariani L">L. Mariani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hientz, K" uniqKey="Hientz K">K. Hientz</name></author><author><name sortKey="Mohr, A" uniqKey="Mohr A">A. Mohr</name></author><author><name sortKey="Bhakta Guha, D" uniqKey="Bhakta Guha D">D. Bhakta-Guha</name></author><author><name sortKey="Efferth, T" uniqKey="Efferth T">T. Efferth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xia, L" uniqKey="Xia L">L. Xia</name></author><author><name sortKey="Tan, S" uniqKey="Tan S">S. Tan</name></author><author><name sortKey="Zhou, Y" uniqKey="Zhou Y">Y. Zhou</name></author><author><name sortKey="Lin, J" uniqKey="Lin J">J. Lin</name></author><author><name sortKey="Wang, H" uniqKey="Wang H">H. Wang</name></author><author><name sortKey="Oyang, L" uniqKey="Oyang L">L. Oyang</name></author><author><name sortKey="Tian, Y" uniqKey="Tian Y">Y. Tian</name></author><author><name sortKey="Liu, L" uniqKey="Liu L">L. Liu</name></author><author><name sortKey="Su, M" uniqKey="Su M">M. Su</name></author><author><name sortKey="Wang, H" uniqKey="Wang H">H. Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanei, T" uniqKey="Tanei T">T. Tanei</name></author><author><name sortKey="Morimoto, K" uniqKey="Morimoto K">K. Morimoto</name></author><author><name sortKey="Shimazu, K" uniqKey="Shimazu K">K. Shimazu</name></author><author><name sortKey="Kim, S J" uniqKey="Kim S">S.J. Kim</name></author><author><name sortKey="Tanji, Y" uniqKey="Tanji Y">Y. Tanji</name></author><author><name sortKey="Taguchi, T" uniqKey="Taguchi T">T. Taguchi</name></author><author><name sortKey="Tamaki, Y" uniqKey="Tamaki Y">Y. Tamaki</name></author><author><name sortKey="Noguchi, S" uniqKey="Noguchi S">S. Noguchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kang, J H" uniqKey="Kang J">J.H. Kang</name></author><author><name sortKey="Lee, S H" uniqKey="Lee S">S.-H. Lee</name></author><author><name sortKey="Hong, D" uniqKey="Hong D">D. Hong</name></author><author><name sortKey="Lee, J S" uniqKey="Lee J">J.-S. Lee</name></author><author><name sortKey="Ahn, H S" uniqKey="Ahn H">H.-S. Ahn</name></author><author><name sortKey="Ahn, J H" uniqKey="Ahn J">J.-H. Ahn</name></author><author><name sortKey="Seong, T W" uniqKey="Seong T">T.W. Seong</name></author><author><name sortKey="Lee, C H" uniqKey="Lee C">C.-H. Lee</name></author><author><name sortKey="Jang, H" uniqKey="Jang H">H. Jang</name></author><author><name sortKey="Hong, K M" uniqKey="Hong K">K.M. Hong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Koppaka, V" uniqKey="Koppaka V">V. Koppaka</name></author><author><name sortKey="Thompson, D C" uniqKey="Thompson D">D.C. Thompson</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y. Chen</name></author><author><name sortKey="Ellermann, M" uniqKey="Ellermann M">M. Ellermann</name></author><author><name sortKey="Nicolaou, K C" uniqKey="Nicolaou K">K.C. Nicolaou</name></author><author><name sortKey="Juvonen, R O" uniqKey="Juvonen R">R.O. Juvonen</name></author><author><name sortKey="Petersen, D" uniqKey="Petersen D">D. Petersen</name></author><author><name sortKey="Deitrich, R A" uniqKey="Deitrich R">R.A. Deitrich</name></author><author><name sortKey="Hurley, T D" uniqKey="Hurley T">T.D. Hurley</name></author><author><name sortKey="Vasiliou, V" uniqKey="Vasiliou V">V. Vasiliou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Venkatesan, S" uniqKey="Venkatesan S">S. Venkatesan</name></author><author><name sortKey="Swanton, C" uniqKey="Swanton C">C. Swanton</name></author><author><name sortKey="Taylor, B S" uniqKey="Taylor B">B.S. Taylor</name></author><author><name sortKey="Costello, J F" uniqKey="Costello J">J.F. Costello</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sever, R" uniqKey="Sever R">R. Sever</name></author><author><name sortKey="Brugge, J S" uniqKey="Brugge J">J.S. Brugge</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Katoh, M" uniqKey="Katoh M">M. Katoh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rothenstein, J M" uniqKey="Rothenstein J">J.M. Rothenstein</name></author><author><name sortKey="Chooback, N" uniqKey="Chooback N">N. Chooback</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gainor, J F" uniqKey="Gainor J">J.F. Gainor</name></author><author><name sortKey="Dardaei, L" uniqKey="Dardaei L">L. Dardaei</name></author><author><name sortKey="Yoda, S" uniqKey="Yoda S">S. Yoda</name></author><author><name sortKey="Friboulet, L" uniqKey="Friboulet L">L. Friboulet</name></author><author><name sortKey="Leshchiner, I" uniqKey="Leshchiner I">I. Leshchiner</name></author><author><name sortKey="Katayama, R" uniqKey="Katayama R">R. Katayama</name></author><author><name sortKey="Dagogo Jack, I" uniqKey="Dagogo Jack I">I. Dagogo-Jack</name></author><author><name sortKey="Gadgeel, S" uniqKey="Gadgeel S">S. Gadgeel</name></author><author><name sortKey="Schultz, K" uniqKey="Schultz K">K. Schultz</name></author><author><name sortKey="Singh, M" uniqKey="Singh M">M. Singh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sun, D" uniqKey="Sun D">D. Sun</name></author><author><name sortKey="Dalin, S" uniqKey="Dalin S">S. Dalin</name></author><author><name sortKey="Hemann, M T" uniqKey="Hemann M">M.T. Hemann</name></author><author><name sortKey="Lauffenburger, D A" uniqKey="Lauffenburger D">D.A. Lauffenburger</name></author><author><name sortKey="Zhao, B" uniqKey="Zhao B">B. Zhao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Amirouchene Angelozzi, N" uniqKey="Amirouchene Angelozzi N">N. Amirouchene-Angelozzi</name></author><author><name sortKey="Swanton, C" uniqKey="Swanton C">C. Swanton</name></author><author><name sortKey="Bardelli, A" uniqKey="Bardelli A">A. Bardelli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Riviere, M K" uniqKey="Riviere M">M.-K. Riviere</name></author><author><name sortKey="Le Tourneau, C" uniqKey="Le Tourneau C">C. Le Tourneau</name></author><author><name sortKey="Paoletti, X" uniqKey="Paoletti X">X. Paoletti</name></author><author><name sortKey="Dubois, F" uniqKey="Dubois F">F. Dubois</name></author><author><name sortKey="Zohar, S" uniqKey="Zohar S">S. Zohar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Day, D" uniqKey="Day D">D. Day</name></author><author><name sortKey="Siu, L L" uniqKey="Siu L">L.L. Siu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mozgunov, P" uniqKey="Mozgunov P">P. Mozgunov</name></author><author><name sortKey="Jaki, T" uniqKey="Jaki T">T. Jaki</name></author><author><name sortKey="Paoletti, X" uniqKey="Paoletti X">X. Paoletti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Paller, C J" uniqKey="Paller C">C.J. Paller</name></author><author><name sortKey="Bradbury, P A" uniqKey="Bradbury P">P.A. Bradbury</name></author><author><name sortKey="Ivy, S P" uniqKey="Ivy S">S.P. Ivy</name></author><author><name sortKey="Seymour, L" uniqKey="Seymour L">L. Seymour</name></author><author><name sortKey="Lorusso, P M" uniqKey="Lorusso P">P.M. LoRusso</name></author><author><name sortKey="Baker, L" uniqKey="Baker L">L. Baker</name></author><author><name sortKey="Rubinstein, L" uniqKey="Rubinstein L">L. Rubinstein</name></author><author><name sortKey="Huang, E" uniqKey="Huang E">E. Huang</name></author><author><name sortKey="Collyar, D" uniqKey="Collyar D">D. Collyar</name></author><author><name sortKey="Groshen, S" uniqKey="Groshen S">S. Groshen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Milella, M" uniqKey="Milella M">M. Milella</name></author><author><name sortKey="Falcone, I" uniqKey="Falcone I">I. Falcone</name></author><author><name sortKey="Conciatori, F" uniqKey="Conciatori F">F. Conciatori</name></author><author><name sortKey="Cesta Incani, U" uniqKey="Cesta Incani U">U. Cesta Incani</name></author><author><name sortKey="Del Curatolo, A" uniqKey="Del Curatolo A">A. Del Curatolo</name></author><author><name sortKey="Inzerilli, N" uniqKey="Inzerilli N">N. Inzerilli</name></author><author><name sortKey="Nuzzo, C M A" uniqKey="Nuzzo C">C.M.A. Nuzzo</name></author><author><name sortKey="Vaccaro, V" uniqKey="Vaccaro V">V. Vaccaro</name></author><author><name sortKey="Vari, S" uniqKey="Vari S">S. Vari</name></author><author><name sortKey="Cognetti, F" uniqKey="Cognetti F">F. Cognetti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singh, S S" uniqKey="Singh S">S.S. Singh</name></author><author><name sortKey="Vats, S" uniqKey="Vats S">S. Vats</name></author><author><name sortKey="Chia, A Y Q" uniqKey="Chia A">A.Y.-Q. Chia</name></author><author><name sortKey="Tan, T Z" uniqKey="Tan T">T.Z. Tan</name></author><author><name sortKey="Deng, S" uniqKey="Deng S">S. Deng</name></author><author><name sortKey="Ong, M S" uniqKey="Ong M">M.S. Ong</name></author><author><name sortKey="Arfuso, F" uniqKey="Arfuso F">F. Arfuso</name></author><author><name sortKey="Yap, C T" uniqKey="Yap C">C.T. Yap</name></author><author><name sortKey="Goh, B C" uniqKey="Goh B">B.C. Goh</name></author><author><name sortKey="Sethi, G" uniqKey="Sethi G">G. Sethi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huang, T" uniqKey="Huang T">T. Huang</name></author><author><name sortKey="Song, X" uniqKey="Song X">X. Song</name></author><author><name sortKey="Yang, Y" uniqKey="Yang Y">Y. Yang</name></author><author><name sortKey="Wan, X" uniqKey="Wan X">X. Wan</name></author><author><name sortKey="Alvarez, A A" uniqKey="Alvarez A">A.A. Alvarez</name></author><author><name sortKey="Sastry, N" uniqKey="Sastry N">N. Sastry</name></author><author><name sortKey="Feng, H" uniqKey="Feng H">H. Feng</name></author><author><name sortKey="Hu, B" uniqKey="Hu B">B. Hu</name></author><author><name sortKey="Cheng, S Y" uniqKey="Cheng S">S.-Y. Cheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Z" uniqKey="Chen Z">Z. Chen</name></author><author><name sortKey="Trotman, L C" uniqKey="Trotman L">L.C. Trotman</name></author><author><name sortKey="Shaffer, D" uniqKey="Shaffer D">D. Shaffer</name></author><author><name sortKey="Lin, H K" uniqKey="Lin H">H.-K. Lin</name></author><author><name sortKey="Dotan, Z A" uniqKey="Dotan Z">Z.A. Dotan</name></author><author><name sortKey="Niki, M" uniqKey="Niki M">M. Niki</name></author><author><name sortKey="Koutcher, J A" uniqKey="Koutcher J">J.A. Koutcher</name></author><author><name sortKey="Scher, H I" uniqKey="Scher H">H.I. Scher</name></author><author><name sortKey="Ludwig, T" uniqKey="Ludwig T">T. Ludwig</name></author><author><name sortKey="Gerald, W" uniqKey="Gerald W">W. Gerald</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brandmaier, A" uniqKey="Brandmaier A">A. Brandmaier</name></author><author><name sortKey="Hou, S Q" uniqKey="Hou S">S.-Q. Hou</name></author><author><name sortKey="Shen, W H" uniqKey="Shen W">W.H. Shen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Paramio, J M" uniqKey="Paramio J">J.M. Paramio</name></author><author><name sortKey="Navarro, M" uniqKey="Navarro M">M. Navarro</name></author><author><name sortKey="Segrelles, C" uniqKey="Segrelles C">C. Segrelles</name></author><author><name sortKey="G Mez Casero, E" uniqKey="G Mez Casero E">E. Gómez-Casero</name></author><author><name sortKey="Jorcano, J L" uniqKey="Jorcano J">J.L. Jorcano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Otto, T" uniqKey="Otto T">T. Otto</name></author><author><name sortKey="Sicinski, P" uniqKey="Sicinski P">P. Sicinski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dick, F A" uniqKey="Dick F">F.A. Dick</name></author><author><name sortKey="Goodrich, D W" uniqKey="Goodrich D">D.W. Goodrich</name></author><author><name sortKey="Sage, J" uniqKey="Sage J">J. Sage</name></author><author><name sortKey="Dyson, N J" uniqKey="Dyson N">N.J. Dyson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Malumbres, M" uniqKey="Malumbres M">M. Malumbres</name></author><author><name sortKey="Barbacid, M" uniqKey="Barbacid M">M. Barbacid</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sherr, C J" uniqKey="Sherr C">C.J. Sherr</name></author><author><name sortKey="Beach, D" uniqKey="Beach D">D. Beach</name></author><author><name sortKey="Shapiro, G I" uniqKey="Shapiro G">G.I. Shapiro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Quereda, V" uniqKey="Quereda V">V. Quereda</name></author><author><name sortKey="Porlan, E" uniqKey="Porlan E">E. Porlan</name></author><author><name sortKey="Ca Amero, M" uniqKey="Ca Amero M">M. Cañamero</name></author><author><name sortKey="Dubus, P" uniqKey="Dubus P">P. Dubus</name></author><author><name sortKey="Malumbres, M" uniqKey="Malumbres M">M. Malumbres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sanidas, I" uniqKey="Sanidas I">I. Sanidas</name></author><author><name sortKey="Morris, R" uniqKey="Morris R">R. Morris</name></author><author><name sortKey="Fella, K A" uniqKey="Fella K">K.A. Fella</name></author><author><name sortKey="Rumde, P H" uniqKey="Rumde P">P.H. Rumde</name></author><author><name sortKey="Boukhali, M" uniqKey="Boukhali M">M. Boukhali</name></author><author><name sortKey="Tai, E C" uniqKey="Tai E">E.C. Tai</name></author><author><name sortKey="Ting, D T" uniqKey="Ting D">D.T. Ting</name></author><author><name sortKey="Lawrence, M S" uniqKey="Lawrence M">M.S. Lawrence</name></author><author><name sortKey="Haas, W" uniqKey="Haas W">W. Haas</name></author><author><name sortKey="Dyson, N J" uniqKey="Dyson N">N.J. Dyson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rigberg, D A" uniqKey="Rigberg D">D.A. Rigberg</name></author><author><name sortKey="Kim, F S" uniqKey="Kim F">F.S. Kim</name></author><author><name sortKey="Sebastian, J L" uniqKey="Sebastian J">J.L. Sebastian</name></author><author><name sortKey="Kazanjian, K K" uniqKey="Kazanjian K">K.K. Kazanjian</name></author><author><name sortKey="Mcfadden, D W" uniqKey="Mcfadden D">D.W. McFadden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roesch, A" uniqKey="Roesch A">A. Roesch</name></author><author><name sortKey="Becker, B" uniqKey="Becker B">B. Becker</name></author><author><name sortKey="Meyer, S" uniqKey="Meyer S">S. Meyer</name></author><author><name sortKey="Hafner, C" uniqKey="Hafner C">C. Hafner</name></author><author><name sortKey="Wild, P J" uniqKey="Wild P">P.J. Wild</name></author><author><name sortKey="Landthaler, M" uniqKey="Landthaler M">M. Landthaler</name></author><author><name sortKey="Vogt, T" uniqKey="Vogt T">T. Vogt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Senderowicz, A M" uniqKey="Senderowicz A">A.M. Senderowicz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deep, A" uniqKey="Deep A">A. Deep</name></author><author><name sortKey="Marwaha, R K" uniqKey="Marwaha R">R.K. Marwaha</name></author><author><name sortKey="Marwaha, M G" uniqKey="Marwaha M">M.G. Marwaha</name></author><author><name sortKey="Jyoti, J" uniqKey="Jyoti J">J. Jyoti</name></author><author><name sortKey="Nandal, R" uniqKey="Nandal R">R. Nandal</name></author><author><name sortKey="Sharma, A K" uniqKey="Sharma A">A.K. Sharma</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Byrd, J C" uniqKey="Byrd J">J.C. Byrd</name></author><author><name sortKey="Shinn, C" uniqKey="Shinn C">C. Shinn</name></author><author><name sortKey="Waselenko, J K" uniqKey="Waselenko J">J.K. Waselenko</name></author><author><name sortKey="Fuchs, E J" uniqKey="Fuchs E">E.J. Fuchs</name></author><author><name sortKey="Lehman, T A" uniqKey="Lehman T">T.A. Lehman</name></author><author><name sortKey="Nguyen, P L" uniqKey="Nguyen P">P.L. Nguyen</name></author><author><name sortKey="Flinn, I W" uniqKey="Flinn I">I.W. Flinn</name></author><author><name sortKey="Diehl, L F" uniqKey="Diehl L">L.F. Diehl</name></author><author><name sortKey="Sausville, E" uniqKey="Sausville E">E. Sausville</name></author><author><name sortKey="Grever, M R" uniqKey="Grever M">M.R. Grever</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Asghar, U" uniqKey="Asghar U">U. Asghar</name></author><author><name sortKey="Witkiewicz, A K" uniqKey="Witkiewicz A">A.K. Witkiewicz</name></author><author><name sortKey="Turner, N C" uniqKey="Turner N">N.C. Turner</name></author><author><name sortKey="Knudsen, E S" uniqKey="Knudsen E">E.S. Knudsen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aklilu, M" uniqKey="Aklilu M">M. Aklilu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Burdette Radoux, S" uniqKey="Burdette Radoux S">S. Burdette-Radoux</name></author><author><name sortKey="Tozer, R G" uniqKey="Tozer R">R.G. Tozer</name></author><author><name sortKey="Lohmann, R C" uniqKey="Lohmann R">R.C. Lohmann</name></author><author><name sortKey="Quirt, I" uniqKey="Quirt I">I. Quirt</name></author><author><name sortKey="Ernst, D S" uniqKey="Ernst D">D.S. Ernst</name></author><author><name sortKey="Walsh, W" uniqKey="Walsh W">W. Walsh</name></author><author><name sortKey="Wainman, N" uniqKey="Wainman N">N. Wainman</name></author><author><name sortKey="Colevas, A D" uniqKey="Colevas A">A.D. Colevas</name></author><author><name sortKey="Eisenhauer, E A" uniqKey="Eisenhauer E">E.A. Eisenhauer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lin, T S" uniqKey="Lin T">T.S. Lin</name></author><author><name sortKey="Howard, O M" uniqKey="Howard O">O.M. Howard</name></author><author><name sortKey="Neuberg, D S" uniqKey="Neuberg D">D.S. Neuberg</name></author><author><name sortKey="Kim, H H" uniqKey="Kim H">H.H. Kim</name></author><author><name sortKey="Shipp, M A" uniqKey="Shipp M">M.A. Shipp</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kouroukis, C T" uniqKey="Kouroukis C">C.T. Kouroukis</name></author><author><name sortKey="Belch, A" uniqKey="Belch A">A. Belch</name></author><author><name sortKey="Crump, M" uniqKey="Crump M">M. Crump</name></author><author><name sortKey="Eisenhauer, E" uniqKey="Eisenhauer E">E. Eisenhauer</name></author><author><name sortKey="Gascoyne, R D" uniqKey="Gascoyne R">R.D. Gascoyne</name></author><author><name sortKey="Meyer, R" uniqKey="Meyer R">R. Meyer</name></author><author><name sortKey="Lohmann, R" uniqKey="Lohmann R">R. Lohmann</name></author><author><name sortKey="Lopez, P" uniqKey="Lopez P">P. Lopez</name></author><author><name sortKey="Powers, J" uniqKey="Powers J">J. Powers</name></author><author><name sortKey="Turner, R" uniqKey="Turner R">R. Turner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Finn, R S" uniqKey="Finn R">R.S. Finn</name></author><author><name sortKey="Crown, J P" uniqKey="Crown J">J.P. Crown</name></author><author><name sortKey="Lang, I" uniqKey="Lang I">I. Lang</name></author><author><name sortKey="Boer, K" uniqKey="Boer K">K. Boer</name></author><author><name sortKey="Bondarenko, I M" uniqKey="Bondarenko I">I.M. Bondarenko</name></author><author><name sortKey="Kulyk, S O" uniqKey="Kulyk S">S.O. Kulyk</name></author><author><name sortKey="Ettl, J" uniqKey="Ettl J">J. Ettl</name></author><author><name sortKey="Patel, R" uniqKey="Patel R">R. Patel</name></author><author><name sortKey="Pinter, T" uniqKey="Pinter T">T. Pinter</name></author><author><name sortKey="Schmidt, M" uniqKey="Schmidt M">M. Schmidt</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Sobhani, N" uniqKey="Sobhani N">N. Sobhani </name></author><author><name sortKey="D Ngelo, A" uniqKey="D Ngelo A">A. D’Angelo</name></author><author><name sortKey="Pittacolo, M" uniqKey="Pittacolo M">M. Pittacolo </name></author><author><name sortKey="Roviello, G" uniqKey="Roviello G">G. Roviello </name></author><author><name sortKey="Miccoli, A" uniqKey="Miccoli A">A. Miccoli </name></author><author><name sortKey="Corona, S P" uniqKey="Corona S">S.P. Corona</name></author><author><name sortKey="Bernocchi, O" uniqKey="Bernocchi O">O. Bernocchi</name></author><author><name sortKey="Generali, D" uniqKey="Generali D">D. Generali</name></author><author><name sortKey="Otto, T" uniqKey="Otto T">T. Otto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shah, M" uniqKey="Shah M">M. Shah</name></author><author><name sortKey="Nunes, M R" uniqKey="Nunes M">M.R. Nunes</name></author><author><name sortKey="Stearns, V" uniqKey="Stearns V">V. Stearns</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Goetz, M P" uniqKey="Goetz M">M.P. Goetz</name></author><author><name sortKey="Toi, M" uniqKey="Toi M">M. Toi</name></author><author><name sortKey="Campone, M" uniqKey="Campone M">M. Campone</name></author><author><name sortKey="Sohn, J" uniqKey="Sohn J">J. Sohn</name></author><author><name sortKey="Paluch Shimon, S" uniqKey="Paluch Shimon S">S. Paluch-Shimon</name></author><author><name sortKey="Huober, J" uniqKey="Huober J">J. Huober</name></author><author><name sortKey="Park, I H" uniqKey="Park I">I.H. Park</name></author><author><name sortKey="Tredan, O" uniqKey="Tredan O">O. Trédan</name></author><author><name sortKey="Chen, S C" uniqKey="Chen S">S.-C. Chen</name></author><author><name sortKey="Manso, L" uniqKey="Manso L">L. Manso</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Portman, N" uniqKey="Portman N">N. Portman</name></author><author><name sortKey="Alexandrou, S" uniqKey="Alexandrou S">S. Alexandrou</name></author><author><name sortKey="Carson, E" uniqKey="Carson E">E. Carson</name></author><author><name sortKey="Wang, S" uniqKey="Wang S">S. Wang</name></author><author><name sortKey="Lim, E" uniqKey="Lim E">E. Lim</name></author><author><name sortKey="Caldon, C E" uniqKey="Caldon C">C.E. Caldon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jabbour Leung, N A" uniqKey="Jabbour Leung N">N.A. Jabbour-Leung</name></author><author><name sortKey="Chen, X" uniqKey="Chen X">X. Chen</name></author><author><name sortKey="Bui, T" uniqKey="Bui T">T. Bui</name></author><author><name sortKey="Jiang, Y" uniqKey="Jiang Y">Y. Jiang</name></author><author><name sortKey="Yang, D" uniqKey="Yang D">D. Yang</name></author><author><name sortKey="Vijayaraghavan, S" uniqKey="Vijayaraghavan S">S. Vijayaraghavan</name></author><author><name sortKey="Mcarthur, M J" uniqKey="Mcarthur M">M.J. McArthur</name></author><author><name sortKey="Hunt, K K" uniqKey="Hunt K">K.K. Hunt</name></author><author><name sortKey="Keyomarsi, K" uniqKey="Keyomarsi K">K. Keyomarsi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hanahan, D" uniqKey="Hanahan D">D. Hanahan</name></author><author><name sortKey="Weinberg, R A" uniqKey="Weinberg R">R.A. Weinberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adams, J M" uniqKey="Adams J">J.M. Adams</name></author><author><name sortKey="Cory, S" uniqKey="Cory S">S. Cory</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stegh, A H" uniqKey="Stegh A">A.H. Stegh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Galluzzi, L" uniqKey="Galluzzi L">L. Galluzzi</name></author><author><name sortKey="Baehrecke, E H" uniqKey="Baehrecke E">E.H. Baehrecke</name></author><author><name sortKey="Ballabio, A" uniqKey="Ballabio A">A. Ballabio</name></author><author><name sortKey="Boya, P" uniqKey="Boya P">P. Boya</name></author><author><name sortKey="Bravo San Pedro, J M" uniqKey="Bravo San Pedro J">J.M. Bravo-San Pedro</name></author><author><name sortKey="Cecconi, F" uniqKey="Cecconi F">F. Cecconi</name></author><author><name sortKey="Choi, A M" uniqKey="Choi A">A.M. Choi</name></author><author><name sortKey="Chu, C T" uniqKey="Chu C">C.T. Chu</name></author><author><name sortKey="Codogno, P" uniqKey="Codogno P">P. Codogno</name></author><author><name sortKey="Colombo, M I" uniqKey="Colombo M">M.I. Colombo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vessoni, A T" uniqKey="Vessoni A">A.T. Vessoni</name></author><author><name sortKey="Filippi Chiela, E C" uniqKey="Filippi Chiela E">E.C. Filippi-Chiela</name></author><author><name sortKey="Menck, C F" uniqKey="Menck C">C.F. Menck</name></author><author><name sortKey="Lenz, G" uniqKey="Lenz G">G. Lenz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hewitt, G" uniqKey="Hewitt G">G. Hewitt</name></author><author><name sortKey="Korolchuk, V I" uniqKey="Korolchuk V">V.I. Korolchuk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kroemer, G" uniqKey="Kroemer G">G. Kroemer</name></author><author><name sortKey="Levine, B" uniqKey="Levine B">B. Levine</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kondapuram, S K" uniqKey="Kondapuram S">S.K. Kondapuram</name></author><author><name sortKey="Sarvagalla, S" uniqKey="Sarvagalla S">S. Sarvagalla</name></author><author><name sortKey="Coumar, M S" uniqKey="Coumar M">M.S. Coumar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Delou, J M A" uniqKey="Delou J">J.M.A. Delou</name></author><author><name sortKey="Biasoli, D" uniqKey="Biasoli D">D. Biasoli</name></author><author><name sortKey="Borges, H L" uniqKey="Borges H">H.L. Borges</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morselli, E" uniqKey="Morselli E">E. Morselli</name></author><author><name sortKey="Galluzzi, L" uniqKey="Galluzzi L">L. Galluzzi</name></author><author><name sortKey="Kepp, O" uniqKey="Kepp O">O. Kepp</name></author><author><name sortKey="Vicencio, J M" uniqKey="Vicencio J">J.-M. Vicencio</name></author><author><name sortKey="Criollo, A" uniqKey="Criollo A">A. Criollo</name></author><author><name sortKey="Maiuri, M C" uniqKey="Maiuri M">M.C. Maiuri</name></author><author><name sortKey="Kroemer, G" uniqKey="Kroemer G">G. Kroemer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shang, L" uniqKey="Shang L">L. Shang</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X. Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ouyang, L" uniqKey="Ouyang L">L. Ouyang</name></author><author><name sortKey="Shi, Z" uniqKey="Shi Z">Z. Shi</name></author><author><name sortKey="Zhao, S" uniqKey="Zhao S">S. Zhao</name></author><author><name sortKey="Wang, F T" uniqKey="Wang F">F.-T. Wang</name></author><author><name sortKey="Zhou, T T" uniqKey="Zhou T">T.-T. Zhou</name></author><author><name sortKey="Liu, B" uniqKey="Liu B">B. Liu</name></author><author><name sortKey="Bao, J K" uniqKey="Bao J">J.-K. Bao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Biasoli, D" uniqKey="Biasoli D">D. Biasoli</name></author><author><name sortKey="Kahn, S A" uniqKey="Kahn S">S.A. Kahn</name></author><author><name sortKey="Cornelio, T A" uniqKey="Cornelio T">T.A. Cornélio</name></author><author><name sortKey="Furtado, M" uniqKey="Furtado M">M. Furtado</name></author><author><name sortKey="Campanati, L" uniqKey="Campanati L">L. Campanati</name></author><author><name sortKey="Chneiweiss, H" uniqKey="Chneiweiss H">H. Chneiweiss</name></author><author><name sortKey="Moura Neto, V" uniqKey="Moura Neto V">V. Moura-Neto</name></author><author><name sortKey="Borges, H L" uniqKey="Borges H">H.L. Borges</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, J" uniqKey="Han J">J. Han</name></author><author><name sortKey="Soletti, R C" uniqKey="Soletti R">R.C. Soletti</name></author><author><name sortKey="Sadarangani, A" uniqKey="Sadarangani A">A. Sadarangani</name></author><author><name sortKey="Sridevi, P" uniqKey="Sridevi P">P. Sridevi</name></author><author><name sortKey="Ramirez, M E" uniqKey="Ramirez M">M.E. Ramirez</name></author><author><name sortKey="Eckmann, L" uniqKey="Eckmann L">L. Eckmann</name></author><author><name sortKey="Borges, H L" uniqKey="Borges H">H.L. Borges</name></author><author><name sortKey="Wang, J Y J" uniqKey="Wang J">J.Y.J. Wang</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Michaloglou, C" uniqKey="Michaloglou C">C. Michaloglou</name></author><author><name sortKey="Crafter, C" uniqKey="Crafter C">C. Crafter</name></author><author><name sortKey="Siersbaek, R" uniqKey="Siersbaek R">R. Siersbaek</name></author><author><name sortKey="Delpuech, O" uniqKey="Delpuech O">O. Delpuech</name></author><author><name sortKey="Curwen, J O" uniqKey="Curwen J">J.O. Curwen</name></author><author><name sortKey="Carnevalli, L S" uniqKey="Carnevalli L">L.S. Carnevalli</name></author><author><name sortKey="Staniszewska, A D" uniqKey="Staniszewska A">A.D. Staniszewska</name></author><author><name sortKey="Polanska, U M" uniqKey="Polanska U">U.M. Polanska</name></author><author><name sortKey="Cheraghchi Bashi, A" uniqKey="Cheraghchi Bashi A">A. Cheraghchi-Bashi</name></author><author><name sortKey="Lawson, M" uniqKey="Lawson M">M. Lawson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berrak, O" uniqKey="Berrak O">O. Berrak</name></author><author><name sortKey="Arisan, E D" uniqKey="Arisan E">E.D. Arisan</name></author><author><name sortKey="Obakan Yerlikaya, P" uniqKey="Obakan Yerlikaya P">P. Obakan-Yerlikaya</name></author><author><name sortKey="Coker Gurkan, A" uniqKey="Coker Gurkan A">A. Coker-Gürkan</name></author><author><name sortKey="Palavan Unsal, N" uniqKey="Palavan Unsal N">N. Palavan-Unsal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, G" uniqKey="Yang G">G. Yang</name></author><author><name sortKey="Nowsheen, S" uniqKey="Nowsheen S">S. Nowsheen</name></author><author><name sortKey="Aziz, K" uniqKey="Aziz K">K. Aziz</name></author><author><name sortKey="Georgakilas, A G" uniqKey="Georgakilas A">A.G. Georgakilas</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Secord, A A" uniqKey="Secord A">A.A. Secord</name></author><author><name sortKey="Teoh, D K" uniqKey="Teoh D">D.K. Teoh</name></author><author><name sortKey="Barry, W T" uniqKey="Barry W">W.T. Barry</name></author><author><name sortKey="Yu, M" uniqKey="Yu M">M. Yu</name></author><author><name sortKey="Broadwater, G" uniqKey="Broadwater G">G. Broadwater</name></author><author><name sortKey="Havrilesky, L J" uniqKey="Havrilesky L">L.J. Havrilesky</name></author><author><name sortKey="Lee, P S" uniqKey="Lee P">P.S. Lee</name></author><author><name sortKey="Berchuck, A" uniqKey="Berchuck A">A. Berchuck</name></author><author><name sortKey="Lancaster, J" uniqKey="Lancaster J">J. Lancaster</name></author><author><name sortKey="Wenham, R M" uniqKey="Wenham R">R.M. Wenham</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Berlin, J" uniqKey="Berlin J">J. Berlin</name></author><author><name sortKey="Ramanathan, R K" uniqKey="Ramanathan R">R.K. Ramanathan</name></author><author><name sortKey="Strickler, J H" uniqKey="Strickler J">J.H. Strickler</name></author><author><name sortKey="Subramaniam, D S" uniqKey="Subramaniam D">D.S. Subramaniam</name></author><author><name sortKey="Marshall, J" uniqKey="Marshall J">J. Marshall</name></author><author><name sortKey="Kang, Y K" uniqKey="Kang Y">Y.-K. Kang</name></author><author><name sortKey="Hetman, R" uniqKey="Hetman R">R. Hetman</name></author><author><name sortKey="Dudley, M W" uniqKey="Dudley M">M.W. Dudley</name></author><author><name sortKey="Zeng, J" uniqKey="Zeng J">J. Zeng</name></author><author><name sortKey="Nickner, C" uniqKey="Nickner C">C. Nickner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Murai, J" uniqKey="Murai J">J. Murai</name></author><author><name sortKey="Pommier, Y" uniqKey="Pommier Y">Y. Pommier</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Pishvaian, M J" uniqKey="Pishvaian M">M.J. Pishvaian</name></author><author><name sortKey="Slack, R S" uniqKey="Slack R">R.S. Slack</name></author><author><name sortKey="Jiang, W" uniqKey="Jiang W">W. Jiang</name></author><author><name sortKey="He, A R" uniqKey="He A">A.R. He</name></author><author><name sortKey="Hwang, J J" uniqKey="Hwang J">J.J. Hwang</name></author><author><name sortKey="Hankin, A" uniqKey="Hankin A">A. Hankin</name></author><author><name sortKey="Dorsch Vogel, K" uniqKey="Dorsch Vogel K">K. Dorsch-Vogel</name></author><author><name sortKey="Kukadiya, D" uniqKey="Kukadiya D">D. Kukadiya</name></author><author><name sortKey="Weiner, L M" uniqKey="Weiner L">L.M. Weiner</name></author><author><name sortKey="Marshall, J L" uniqKey="Marshall J">J.L. Marshall</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Yoshino, T" uniqKey="Yoshino T">T. Yoshino</name></author><author><name sortKey="Uetake, H" uniqKey="Uetake H">H. Uetake</name></author><author><name sortKey="Tsuchihara, K" uniqKey="Tsuchihara K">K. Tsuchihara</name></author><author><name sortKey="Shitara, K" uniqKey="Shitara K">K. Shitara</name></author><author><name sortKey="Yamazaki, K" uniqKey="Yamazaki K">K. Yamazaki</name></author><author><name sortKey="Oki, E" uniqKey="Oki E">E. Oki</name></author><author><name sortKey="Sato, T" uniqKey="Sato T">T. Sato</name></author><author><name sortKey="Naitoh, T" uniqKey="Naitoh T">T. Naitoh</name></author><author><name sortKey="Komatsu, Y" uniqKey="Komatsu Y">Y. Komatsu</name></author><author><name sortKey="Kato, T" uniqKey="Kato T">T. Kato</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Hauke, R J" uniqKey="Hauke R">R.J. Hauke</name></author><author><name sortKey="Infante, J R" uniqKey="Infante J">J.R. Infante</name></author><author><name sortKey="Rubin, M S" uniqKey="Rubin M">M.S. Rubin</name></author><author><name sortKey="Shih, K C" uniqKey="Shih K">K.C. Shih</name></author><author><name sortKey="Arrowsmith, E R" uniqKey="Arrowsmith E">E.R. Arrowsmith</name></author><author><name sortKey="Hainsworth, J D" uniqKey="Hainsworth J">J.D. Hainsworth</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Zelenetz, A D" uniqKey="Zelenetz A">A.D. Zelenetz</name></author><author><name sortKey="Barrientos, J C" uniqKey="Barrientos J">J.C. Barrientos</name></author><author><name sortKey="Brown, J R" uniqKey="Brown J">J.R. Brown</name></author><author><name sortKey="Coiffier, B" uniqKey="Coiffier B">B. Coiffier</name></author><author><name sortKey="Delgado, J" uniqKey="Delgado J">J. Delgado</name></author><author><name sortKey="Egyed, M" uniqKey="Egyed M">M. Egyed</name></author><author><name sortKey="Ghia, P" uniqKey="Ghia P">P. Ghia</name></author><author><name sortKey="Illes, A" uniqKey="Illes A">Á. Illés</name></author><author><name sortKey="Jurczak, W" uniqKey="Jurczak W">W. Jurczak</name></author><author><name sortKey="Marlton, P" uniqKey="Marlton P">P. Marlton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dunn, L A" uniqKey="Dunn L">L.A. Dunn</name></author><author><name sortKey="Fury, M G" uniqKey="Fury M">M.G. Fury</name></author><author><name sortKey="Xiao, H" uniqKey="Xiao H">H. Xiao</name></author><author><name sortKey="Baxi, S S" uniqKey="Baxi S">S.S. Baxi</name></author><author><name sortKey="Sherman, E J" uniqKey="Sherman E">E.J. Sherman</name></author><author><name sortKey="Korte, S" uniqKey="Korte S">S. Korte</name></author><author><name sortKey="Pfister, C" uniqKey="Pfister C">C. Pfister</name></author><author><name sortKey="Haque, S" uniqKey="Haque S">S. Haque</name></author><author><name sortKey="Katabi, N" uniqKey="Katabi N">N. Katabi</name></author><author><name sortKey="Ho, A L" uniqKey="Ho A">A.L. Ho</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Mcwilliams, R R" uniqKey="Mcwilliams R">R.R. McWilliams</name></author><author><name sortKey="Allred, J B" uniqKey="Allred J">J.B. Allred</name></author><author><name sortKey="Slostad, J A" uniqKey="Slostad J">J.A. Slostad</name></author><author><name sortKey="Katipamula, R" uniqKey="Katipamula R">R. Katipamula</name></author><author><name sortKey="Dronca, R S" uniqKey="Dronca R">R.S. Dronca</name></author><author><name sortKey="Rumilla, K M" uniqKey="Rumilla K">K.M. Rumilla</name></author><author><name sortKey="Erickson, L A" uniqKey="Erickson L">L.A. Erickson</name></author><author><name sortKey="Bryce, A H" uniqKey="Bryce A">A.H. Bryce</name></author><author><name sortKey="Joseph, R W" uniqKey="Joseph R">R.W. Joseph</name></author><author><name sortKey="Kottschade, L A" uniqKey="Kottschade L">L.A. Kottschade</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Van Den Bent, M J" uniqKey="Van Den Bent M">M.J. Van den Bent</name></author><author><name sortKey="Klein, M" uniqKey="Klein M">M. Klein</name></author><author><name sortKey="Smits, M" uniqKey="Smits M">M. Smits</name></author><author><name sortKey="Reijneveld, J C" uniqKey="Reijneveld J">J.C. Reijneveld</name></author><author><name sortKey="French, P J" uniqKey="French P">P.J. French</name></author><author><name sortKey="Clement, P" uniqKey="Clement P">P. Clement</name></author><author><name sortKey="De Vos, F Y F" uniqKey="De Vos F">F.Y.F. de Vos</name></author><author><name sortKey="Wick, A" uniqKey="Wick A">A. Wick</name></author><author><name sortKey="Mulholland, P J" uniqKey="Mulholland P">P.J. Mulholland</name></author><author><name sortKey="Taphoorn, M J B" uniqKey="Taphoorn M">M.J.B. Taphoorn</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Santoro, A" uniqKey="Santoro A">A. Santoro</name></author><author><name sortKey="Su, W C" uniqKey="Su W">W.-C. Su</name></author><author><name sortKey="Navarro, A" uniqKey="Navarro A">A. Navarro</name></author><author><name sortKey="Simonelli, M" uniqKey="Simonelli M">M. Simonelli</name></author><author><name sortKey="Yang, J C H" uniqKey="Yang J">J.C.-H. Yang</name></author><author><name sortKey="Ardizzoni, A" uniqKey="Ardizzoni A">A. Ardizzoni</name></author><author><name sortKey="Barlesi, F" uniqKey="Barlesi F">F. Barlesi</name></author><author><name sortKey="Kang, J H" uniqKey="Kang J">J.H. Kang</name></author><author><name sortKey="Didominick, S" uniqKey="Didominick S">S. Didominick</name></author><author><name sortKey="Abdelhady, A" uniqKey="Abdelhady A">A. Abdelhady</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wood, A C" uniqKey="Wood A">A.C. Wood</name></author><author><name sortKey="Krytska, K" uniqKey="Krytska K">K. Krytska</name></author><author><name sortKey="Ryles, H T" uniqKey="Ryles H">H.T. Ryles</name></author><author><name sortKey="Infarinato, N R" uniqKey="Infarinato N">N.R. Infarinato</name></author><author><name sortKey="Sano, R" uniqKey="Sano R">R. Sano</name></author><author><name sortKey="Hansel, T D" uniqKey="Hansel T">T.D. Hansel</name></author><author><name sortKey="Hart, L S" uniqKey="Hart L">L.S. Hart</name></author><author><name sortKey="King, F J" uniqKey="King F">F.J. King</name></author><author><name sortKey="Smith, T R" uniqKey="Smith T">T.R. Smith</name></author><author><name sortKey="Ainscow, E" uniqKey="Ainscow E">E. Ainscow</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Tripathi, A" uniqKey="Tripathi A">A. Tripathi</name></author><author><name sortKey="Supko, J G" uniqKey="Supko J">J.G. Supko</name></author><author><name sortKey="Gray, K P" uniqKey="Gray K">K.P. Gray</name></author><author><name sortKey="Melnick, Z" uniqKey="Melnick Z">Z. Melnick</name></author><author><name sortKey="Taplin, M E" uniqKey="Taplin M">M.-E. Taplin</name></author><author><name sortKey="Choudhury, A D" uniqKey="Choudhury A">A.D. Choudhury</name></author><author><name sortKey="Pomerantz, M" uniqKey="Pomerantz M">M. Pomerantz</name></author><author><name sortKey="Bellmunt, J" uniqKey="Bellmunt J">J. Bellmunt</name></author><author><name sortKey="Yu, C" uniqKey="Yu C">C. Yu</name></author><author><name sortKey="Sun, Z" uniqKey="Sun Z">Z. Sun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kato, S" uniqKey="Kato S">S. Kato</name></author><author><name sortKey="Jardim, D L" uniqKey="Jardim D">D.L. Jardim</name></author><author><name sortKey="Johnson, F M" uniqKey="Johnson F">F.M. Johnson</name></author><author><name sortKey="Subbiah, V" uniqKey="Subbiah V">V. Subbiah</name></author><author><name sortKey="Piha Paul, S" uniqKey="Piha Paul S">S. Piha-Paul</name></author><author><name sortKey="Tsimberidou, A M" uniqKey="Tsimberidou A">A.M. Tsimberidou</name></author><author><name sortKey="Falchook, G S" uniqKey="Falchook G">G.S. Falchook</name></author><author><name sortKey="Karp, D" uniqKey="Karp D">D. Karp</name></author><author><name sortKey="Zinner, R" uniqKey="Zinner R">R. Zinner</name></author><author><name sortKey="Wheler, J" uniqKey="Wheler J">J. Wheler</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Michmerhuizen, N L" uniqKey="Michmerhuizen N">N.L. Michmerhuizen</name></author><author><name sortKey="Leonard, E" uniqKey="Leonard E">E. Leonard</name></author><author><name sortKey="Matovina, C" uniqKey="Matovina C">C. Matovina</name></author><author><name sortKey="Harris, M" uniqKey="Harris M">M. Harris</name></author><author><name sortKey="Herbst, G" uniqKey="Herbst G">G. Herbst</name></author><author><name sortKey="Kulkarni, A" uniqKey="Kulkarni A">A. Kulkarni</name></author><author><name sortKey="Zhai, J" uniqKey="Zhai J">J. Zhai</name></author><author><name sortKey="Jiang, H" uniqKey="Jiang H">H. Jiang</name></author><author><name sortKey="Carey, T E" uniqKey="Carey T">T.E. Carey</name></author><author><name sortKey="Brenner, J C" uniqKey="Brenner J">J.C. Brenner</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Barr, P M" uniqKey="Barr P">P.M. Barr</name></author><author><name sortKey="Saylors, G B" uniqKey="Saylors G">G.B. Saylors</name></author><author><name sortKey="Spurgeon, S E" uniqKey="Spurgeon S">S.E. Spurgeon</name></author><author><name sortKey="Cheson, B D" uniqKey="Cheson B">B.D. Cheson</name></author><author><name sortKey="Greenwald, D R" uniqKey="Greenwald D">D.R. Greenwald</name></author><author><name sortKey="Obrien, S M" uniqKey="Obrien S">S.M. OBrien</name></author><author><name sortKey="Liem, A K D" uniqKey="Liem A">A.K.D. Liem</name></author><author><name sortKey="Mclntyre, R E" uniqKey="Mclntyre R">R.E. Mclntyre</name></author><author><name sortKey="Joshi, A" uniqKey="Joshi A">A. Joshi</name></author><author><name sortKey="Abella Dominicis, E" uniqKey="Abella Dominicis E">E. Abella-Dominicis</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Keam, B" uniqKey="Keam B">B. Keam</name></author><author><name sortKey="Tahara, M" uniqKey="Tahara M">M. Tahara</name></author><author><name sortKey="Lin, J C" uniqKey="Lin J">J.-C. Lin</name></author><author><name sortKey="Sacco, A G" uniqKey="Sacco A">A.G. Sacco</name></author><author><name sortKey="Melichar, B" uniqKey="Melichar B">B. Melichar</name></author><author><name sortKey="Baney, T" uniqKey="Baney T">T. Baney</name></author><author><name sortKey="Hoffman, J" uniqKey="Hoffman J">J. Hoffman</name></author><author><name sortKey="Wang, D D" uniqKey="Wang D">D.D. Wang</name></author><author><name sortKey="Wang, S L" uniqKey="Wang S">S.L. Wang</name></author><author><name sortKey="Martini, J F" uniqKey="Martini J">J.-F. Martini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sullivan, R J" uniqKey="Sullivan R">R.J. Sullivan</name></author><author><name sortKey="Amaria, R N" uniqKey="Amaria R">R.N. Amaria</name></author><author><name sortKey="Lawrence, D P" uniqKey="Lawrence D">D.P. Lawrence</name></author><author><name sortKey="Brennan, J" uniqKey="Brennan J">J. Brennan</name></author><author><name sortKey="Leister, C" uniqKey="Leister C">C. Leister</name></author><author><name sortKey="Singh, R" uniqKey="Singh R">R. Singh</name></author><author><name sortKey="Legos, J" uniqKey="Legos J">J. Legos</name></author><author><name sortKey="Thurm, H" uniqKey="Thurm H">H. Thurm</name></author><author><name sortKey="Yan, L" uniqKey="Yan L">L. Yan</name></author><author><name sortKey="Flaherty, K T" uniqKey="Flaherty K">K.T. Flaherty</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Berghoff, A S" uniqKey="Berghoff A">A.S. Berghoff</name></author><author><name sortKey="Preusser, M" uniqKey="Preusser M">M. Preusser</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Nissan, M H" uniqKey="Nissan M">M.H. Nissan</name></author><author><name sortKey="Rosen, N" uniqKey="Rosen N">N. Rosen</name></author><author><name sortKey="Solit, D B" uniqKey="Solit D">D.B. Solit</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Flaherty, K T" uniqKey="Flaherty K">K.T. Flaherty</name></author><author><name sortKey="Infante, J R" uniqKey="Infante J">J.R. Infante</name></author><author><name sortKey="Daud, A" uniqKey="Daud A">A. Daud</name></author><author><name sortKey="Gonzalez, R" uniqKey="Gonzalez R">R. Gonzalez</name></author><author><name sortKey="Kefford, R F" uniqKey="Kefford R">R.F. Kefford</name></author><author><name sortKey="Sosman, J" uniqKey="Sosman J">J. Sosman</name></author><author><name sortKey="Hamid, O" uniqKey="Hamid O">O. Hamid</name></author><author><name sortKey="Schuchter, L" uniqKey="Schuchter L">L. Schuchter</name></author><author><name sortKey="Cebon, J" uniqKey="Cebon J">J. Cebon</name></author><author><name sortKey="Ibrahim, N" uniqKey="Ibrahim N">N. Ibrahim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pelster, M S" uniqKey="Pelster M">M.S. Pelster</name></author><author><name sortKey="Amaria, R N" uniqKey="Amaria R">R.N. Amaria</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jaiswal, B S" uniqKey="Jaiswal B">B.S. Jaiswal</name></author><author><name sortKey="Durinck, S" uniqKey="Durinck S">S. Durinck</name></author><author><name sortKey="Stawiski, E W" uniqKey="Stawiski E">E.W. Stawiski</name></author><author><name sortKey="Yin, J" uniqKey="Yin J">J. Yin</name></author><author><name sortKey="Wang, W" uniqKey="Wang W">W. Wang</name></author><author><name sortKey="Lin, E" uniqKey="Lin E">E. Lin</name></author><author><name sortKey="Moffat, J" uniqKey="Moffat J">J. Moffat</name></author><author><name sortKey="Martin, S E" uniqKey="Martin S">S.E. Martin</name></author><author><name sortKey="Modrusan, Z" uniqKey="Modrusan Z">Z. Modrusan</name></author><author><name sortKey="Seshagiri, S" uniqKey="Seshagiri S">S. Seshagiri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sullivan, R J" uniqKey="Sullivan R">R.J. Sullivan</name></author><author><name sortKey="Infante, J R" uniqKey="Infante J">J.R. Infante</name></author><author><name sortKey="Janku, F" uniqKey="Janku F">F. Janku</name></author><author><name sortKey="Lee Wong, D J" uniqKey="Lee Wong D">D.J. Lee Wong</name></author><author><name sortKey="Sosman, J A" uniqKey="Sosman J">J.A. Sosman</name></author><author><name sortKey="Keedy, V" uniqKey="Keedy V">V. Keedy</name></author><author><name sortKey="Patel, M R" uniqKey="Patel M">M.R. Patel</name></author><author><name sortKey="Shapiro, G I" uniqKey="Shapiro G">G.I. Shapiro</name></author><author><name sortKey="Mier, J W" uniqKey="Mier J">J.W. Mier</name></author><author><name sortKey="Tolcher, A W" uniqKey="Tolcher A">A.W. Tolcher</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Janku, F" uniqKey="Janku F">F. Janku</name></author><author><name sortKey="Yap, T A" uniqKey="Yap T">T.A. Yap</name></author><author><name sortKey="Meric Bernstam, F" uniqKey="Meric Bernstam F">F. Meric-Bernstam</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hanker, A B" uniqKey="Hanker A">A.B. Hanker</name></author><author><name sortKey="Kaklamani, V" uniqKey="Kaklamani V">V. Kaklamani</name></author><author><name sortKey="Arteaga, C L" uniqKey="Arteaga C">C.L. Arteaga</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Curigliano, G" uniqKey="Curigliano G">G. Curigliano</name></author><author><name sortKey="Shah, R R" uniqKey="Shah R">R.R. Shah</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Song, M" uniqKey="Song M">M. Song</name></author><author><name sortKey="Bode, A M" uniqKey="Bode A">A.M. Bode</name></author><author><name sortKey="Dong, Z" uniqKey="Dong Z">Z. Dong</name></author><author><name sortKey="Lee, M H" uniqKey="Lee M">M.H. Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sampath, D" uniqKey="Sampath D">D. Sampath</name></author><author><name sortKey="Malik, A" uniqKey="Malik A">A. Malik</name></author><author><name sortKey="Plunkett, W" uniqKey="Plunkett W">W. Plunkett</name></author><author><name sortKey="Nowak, B" uniqKey="Nowak B">B. Nowak</name></author><author><name sortKey="Williams, B" uniqKey="Williams B">B. Williams</name></author><author><name sortKey="Burton, M" uniqKey="Burton M">M. Burton</name></author><author><name sortKey="Verstovsek, S" uniqKey="Verstovsek S">S. Verstovsek</name></author><author><name sortKey="Faderl, S" uniqKey="Faderl S">S. Faderl</name></author><author><name sortKey="Garcia Manero, G" uniqKey="Garcia Manero G">G. Garcia-Manero</name></author><author><name sortKey="List, A F" uniqKey="List A">A.F. List</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sunyoto, T" uniqKey="Sunyoto T">T. Sunyoto</name></author><author><name sortKey="Potet, J" uniqKey="Potet J">J. Potet</name></author><author><name sortKey="Boelaert, M" uniqKey="Boelaert M">M. Boelaert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ghidini, M" uniqKey="Ghidini M">M. Ghidini</name></author><author><name sortKey="Petrelli, F" uniqKey="Petrelli F">F. Petrelli</name></author><author><name sortKey="Ghidini, A" uniqKey="Ghidini A">A. Ghidini</name></author><author><name sortKey="Tomasello, G" uniqKey="Tomasello G">G. Tomasello</name></author><author><name sortKey="Hahne, J C" uniqKey="Hahne J">J.C. Hahne</name></author><author><name sortKey="Passalacqua, R" uniqKey="Passalacqua R">R. Passalacqua</name></author><author><name sortKey="Barni, S" uniqKey="Barni S">S. Barni</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Teng, Q X" uniqKey="Teng Q">Q.-X. Teng</name></author><author><name sortKey="Ashar, Y V" uniqKey="Ashar Y">Y.V. Ashar</name></author><author><name sortKey="Gupta, P" uniqKey="Gupta P">P. Gupta</name></author><author><name sortKey="Gadee, E" uniqKey="Gadee E">E. Gadee</name></author><author><name sortKey="Fan, Y F" uniqKey="Fan Y">Y.-F. Fan</name></author><author><name sortKey="Reznik, S E" uniqKey="Reznik S">S.E. Reznik</name></author><author><name sortKey="Wurpel, J N D" uniqKey="Wurpel J">J.N.D. Wurpel</name></author><author><name sortKey="Chen, Z S" uniqKey="Chen Z">Z.-S. Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prasad, V" uniqKey="Prasad V">V. Prasad</name></author><author><name sortKey="De Jesus, K" uniqKey="De Jesus K">K. De Jesús</name></author><author><name sortKey="Mailankody, S" uniqKey="Mailankody S">S. Mailankody</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Turk, A A" uniqKey="Turk A">A.A. Turk</name></author><author><name sortKey="Wisinski, K B" uniqKey="Wisinski K">K.B. Wisinski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Helleday, T" uniqKey="Helleday T">T. Helleday</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Heinzel, A" uniqKey="Heinzel A">A. Heinzel</name></author><author><name sortKey="Marhold, M" uniqKey="Marhold M">M. Marhold</name></author><author><name sortKey="Mayer, P" uniqKey="Mayer P">P. Mayer</name></author><author><name sortKey="Schwarz, M" uniqKey="Schwarz M">M. Schwarz</name></author><author><name sortKey="Tomasich, E" uniqKey="Tomasich E">E. Tomasich</name></author><author><name sortKey="Lukas, A" uniqKey="Lukas A">A. Lukas</name></author><author><name sortKey="Krainer, M" uniqKey="Krainer M">M. Krainer</name></author><author><name sortKey="Perco, P" uniqKey="Perco P">P. Perco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gupta, S C" uniqKey="Gupta S">S.C. Gupta</name></author><author><name sortKey="Sung, B" uniqKey="Sung B">B. Sung</name></author><author><name sortKey="Prasad, S" uniqKey="Prasad S">S. Prasad</name></author><author><name sortKey="Webb, L J" uniqKey="Webb L">L.J. Webb</name></author><author><name sortKey="Aggarwal, B B" uniqKey="Aggarwal B">B.B. Aggarwal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bertolini, F" uniqKey="Bertolini F">F. Bertolini</name></author><author><name sortKey="Sukhatme, V P" uniqKey="Sukhatme V">V.P. Sukhatme</name></author><author><name sortKey="Bouche, G" uniqKey="Bouche G">G. Bouche</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, X" uniqKey="Wang X">X. Wang</name></author><author><name sortKey="Shen, C" uniqKey="Shen C">C. Shen</name></author><author><name sortKey="Liu, Z" uniqKey="Liu Z">Z. Liu</name></author><author><name sortKey="Peng, F" uniqKey="Peng F">F. Peng</name></author><author><name sortKey="Chen, X" uniqKey="Chen X">X. Chen</name></author><author><name sortKey="Yang, G" uniqKey="Yang G">G. Yang</name></author><author><name sortKey="Zhang, D" uniqKey="Zhang D">D. Zhang</name></author><author><name sortKey="Yin, Z" uniqKey="Yin Z">Z. Yin</name></author><author><name sortKey="Ma, J" uniqKey="Ma J">J. Ma</name></author><author><name sortKey="Zheng, Z" uniqKey="Zheng Z">Z. Zheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hendouei, N" uniqKey="Hendouei N">N. Hendouei</name></author><author><name sortKey="Saghafi, F" uniqKey="Saghafi F">F. Saghafi</name></author><author><name sortKey="Shadfar, F" uniqKey="Shadfar F">F. Shadfar</name></author><author><name sortKey="Hosseinimehr, S J" uniqKey="Hosseinimehr S">S.J. Hosseinimehr</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, W Y" uniqKey="Lee W">W.-Y. Lee</name></author><author><name sortKey="Lee, W T" uniqKey="Lee W">W.-T. Lee</name></author><author><name sortKey="Cheng, C H" uniqKey="Cheng C">C.-H. Cheng</name></author><author><name sortKey="Chen, K C" uniqKey="Chen K">K.-C. Chen</name></author><author><name sortKey="Chou, C M" uniqKey="Chou C">C.-M. Chou</name></author><author><name sortKey="Chung, C H" uniqKey="Chung C">C.-H. Chung</name></author><author><name sortKey="Sun, M S" uniqKey="Sun M">M.-S. Sun</name></author><author><name sortKey="Cheng, H W" uniqKey="Cheng H">H.-W. Cheng</name></author><author><name sortKey="Ho, M N" uniqKey="Ho M">M.-N. Ho</name></author><author><name sortKey="Lin, C W" uniqKey="Lin C">C.-W. Lin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Soletti, R C" uniqKey="Soletti R">R.C. Soletti</name></author><author><name sortKey="Biasoli, D" uniqKey="Biasoli D">D. Biasoli</name></author><author><name sortKey="Rodrigues, N A L V" uniqKey="Rodrigues N">N.A.L.V. Rodrigues</name></author><author><name sortKey="Delou, J M A" uniqKey="Delou J">J.M.A. Delou</name></author><author><name sortKey="Maciel, R" uniqKey="Maciel R">R. Maciel</name></author><author><name sortKey="Chagas, V L A" uniqKey="Chagas V">V.L.A. Chagas</name></author><author><name sortKey="Martins, R A P" uniqKey="Martins R">R.A.P. Martins</name></author><author><name sortKey="Rehen, S K" uniqKey="Rehen S">S.K. Rehen</name></author><author><name sortKey="Borges, H L" uniqKey="Borges H">H.L. Borges</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Laurent, M" uniqKey="Laurent M">M. Laurent</name></author><author><name sortKey="Brahmi, M" uniqKey="Brahmi M">M. Brahmi</name></author><author><name sortKey="Dufresne, A" uniqKey="Dufresne A">A. Dufresne</name></author><author><name sortKey="Meeus, P" uniqKey="Meeus P">P. Meeus</name></author><author><name sortKey="Karanian, M" uniqKey="Karanian M">M. Karanian</name></author><author><name sortKey="Ray Coquard, I" uniqKey="Ray Coquard I">I. Ray-Coquard</name></author><author><name sortKey="Blay, J Y" uniqKey="Blay J">J.-Y. Blay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brown, A S" uniqKey="Brown A">A.S. Brown</name></author><author><name sortKey="Patel, C J" uniqKey="Patel C">C.J. Patel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aberle, M R" uniqKey="Aberle M">M.R. Aberle</name></author><author><name sortKey="Burkhart, R A" uniqKey="Burkhart R">R.A. Burkhart</name></author><author><name sortKey="Tiriac, H" uniqKey="Tiriac H">H. Tiriac</name></author><author><name sortKey="Olde Damink, S W M" uniqKey="Olde Damink S">S.W.M. Olde Damink</name></author><author><name sortKey="Dejong, C H C" uniqKey="Dejong C">C.H.C. Dejong</name></author><author><name sortKey="Tuveson, D A" uniqKey="Tuveson D">D.A. Tuveson</name></author><author><name sortKey="Van Dam, R M" uniqKey="Van Dam R">R.M. van Dam</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cells</journal-id><journal-id journal-id-type="iso-abbrev">Cells</journal-id><journal-id journal-id-type="publisher-id">cells</journal-id><journal-title-group><journal-title>Cells</journal-title></journal-title-group><issn pub-type="epub">2073-4409</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31480389</article-id><article-id pub-id-type="pmc">6770082</article-id><article-id pub-id-type="doi">10.3390/cells8091013</article-id><article-id pub-id-type="publisher-id">cells-08-01013</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Highlights in Resistance Mechanism Pathways for Combination Therapy</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-1141-5351</contrib-id><name><surname>Delou</surname><given-names>João M. A.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Souza</surname><given-names>Alana S. O.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Souza</surname><given-names>Leonel C. M.</given-names></name></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-2866-4223</contrib-id><name><surname>Borges</surname><given-names>Helena L.</given-names></name><xref rid="c1-cells-08-01013" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-cells-08-01013">Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil</aff><author-notes><corresp id="c1-cells-08-01013"><label>*</label>Correspondence: <email>hborges@icb.ufrj.br</email>; Tel.: +55-21-39386467</corresp></author-notes><pub-date pub-type="epub"><day>30</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>9</month><year>2019</year></pub-date><volume>8</volume><issue>9</issue><elocation-id>1013</elocation-id><history><date date-type="received"><day>15</day><month>7</month><year>2019</year></date><date date-type="accepted"><day>20</day><month>8</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Combination chemotherapy has been a mainstay in cancer treatment for the last 60 years. Although the mechanisms of action and signaling pathways affected by most treatments with single antineoplastic agents might be relatively well understood, most combinations remain poorly understood. This review presents the most common alterations of signaling pathways in response to cytotoxic and targeted anticancer drug treatments, with a discussion of how the knowledge of signaling pathways might support and orient the development of innovative strategies for anticancer combination therapy. The ultimate goal is to highlight possible strategies of chemotherapy combinations based on the signaling pathways associated with the resistance mechanisms against anticancer drugs to maximize the selective induction of cancer cell death. We consider this review an extensive compilation of updated known information on chemotherapy resistance mechanisms to promote new combination therapies to be to discussed and tested.</p></abstract><kwd-group><kwd>resistance mechanisms</kwd><kwd>hallmarks of cancer</kwd><kwd>targeted therapy</kwd><kwd>cytotoxic chemotherapy</kwd><kwd>drugs mechanisms of action</kwd><kwd>cell death</kwd></kwd-group></article-meta></front><body><sec sec-type="intro" id="sec1-cells-08-01013"><title>1. Introduction</title><p>Cancer chemotherapy has evolved greatly since the first clinical trial using nitrogen mustard in 1942 [<xref rid="B1-cells-08-01013" ref-type="bibr">1</xref>]. This single-agent treatment, or monotherapy, gave rise to the study, screening, and development of several other small molecules as anticancer candidates. In the 1960s, the use of the combination of <underline>V</underline>incristine, <underline>A</underline>methopterin, 6-<underline>M</underline>ercaptopurine, and <underline>P</underline>rednisone (VAMP) for pediatric leukemia markedly changed the stigmatic status of cancer chemotherapy to “curable”, showing drastic increments in remissions and survival. It also made evident the superiority of drug combination over monotherapy [<xref rid="B2-cells-08-01013" ref-type="bibr">2</xref>]. However, the underlying mechanisms for the efficacy achieved with this combination therapy were unclear at the time and, in part, remain so today. Combination therapy aims to hamper cancer cell homeostasis/metabolism at multiple simultaneous targets to improve its therapeutic efficacy, reduce dosage, reduce side effects, and prevent or delay the development of acquired resistance [<xref rid="B3-cells-08-01013" ref-type="bibr">3</xref>]. However, acquired resistance will still eventually develop along with the treatment in response to the exposure to antineoplastic drugs. </p><p>Tumor cells can develop drug resistance due to intrinsic factors, such as mutations, translocations, epigenetic elements, and extrinsic factors, such as hypoxia, pH, hormones, cytokines from its microenvironment surroundings, and antineoplastic agents [<xref rid="B4-cells-08-01013" ref-type="bibr">4</xref>]. The tumor heterogeneity and mutational load have been directly associated with the emergence of acquired resistance to antitumor drugs [<xref rid="B5-cells-08-01013" ref-type="bibr">5</xref>,<xref rid="B6-cells-08-01013" ref-type="bibr">6</xref>]. Chemotherapeutic agents from diverse drug classifications have been combined to bypass multiple factors of drug resistance. </p><p>There is a growing concern with the chemical structure-based classification generally used by pharmacology texts and the restricted mindset it provides in combinatorial preclinical studies. The classification of drugs as cell cycle-dependent or independent was the first phenotype-based classification of antitumor agents [<xref rid="B7-cells-08-01013" ref-type="bibr">7</xref>,<xref rid="B8-cells-08-01013" ref-type="bibr">8</xref>]. Biological targets [<xref rid="B9-cells-08-01013" ref-type="bibr">9</xref>], biological activities [<xref rid="B10-cells-08-01013" ref-type="bibr">10</xref>], and structural prediction of antiproliferative activity [<xref rid="B11-cells-08-01013" ref-type="bibr">11</xref>] have also been proposed to facilitate insights into new drug combinations. Here we harvested the target information and biological activity to propose a rationale for drug combination.</p><p>Recent work with an RNAi-based high-throughput screening of combinations of antitumor drug libraries in cultures of almost every cancer type cell known [<xref rid="B12-cells-08-01013" ref-type="bibr">12</xref>] has reached a surprising conclusion. Pritchard and coauthors have claimed that most of the combination protocols approved since are, in fact, almost as good as single-agent treatments, with some few or almost negligible mechanistic contributions from single-drug components. Very few combinations exhibited real synergism. The authors suggested that each drug might affect different heterogeneous subpopulations. When the drug cocktail affects the same cell, the convergence of downstream signaling pathways related to cell death might limit the efficiency of the combined treatment [<xref rid="B12-cells-08-01013" ref-type="bibr">12</xref>].</p><p>The use of medications with different targets but with some overlap in their resistance-related signaling pathways might improve efficiency. Here we propose a strategy for combination studies that one of the drugs used in the antitumor cocktail should be an inhibitor of a known resistance signaling pathway of one or more drugs used in combination. The purpose of the discussion is to improve the discovery of drug combination studies. To improve the understanding of specific resistance mechanisms of widely used anticancer drugs is necessary. The information on resistance mechanisms, signaling pathways, and mechanisms of action for cytotoxic and target therapy is summarized in tables and discussed below.</p></sec><sec id="sec2-cells-08-01013"><title>2. Search Strategy</title><p>We highlighted the most clinically relevant information from selected articles (Pubmed), clinical trials (ClinicalTrials.gov), and the curated databases Drugbank [<xref rid="B13-cells-08-01013" ref-type="bibr">13</xref>] and SuperCYP/Transformer [<xref rid="B14-cells-08-01013" ref-type="bibr">14</xref>] relating to drug resistance mechanisms.</p><p>Drug names were used as keywords, as well as, but not restricted to target, off-target, mechanism of action, resistance, mechanism of resistance, signaling pathway, detoxification, elimination, metabolism, pharmacokinetics, pharmacodynamics, absorption, distribution, binding, clinical trial, combination, synthetic lethality, drug combination, Food and Drug Administration (FDA) approval, screening, combination screening, and drug screening.</p><p>Although extensive pharmacokinetic studies are required for the approval of a drug for human use, it is not mandatory to completely elucidate every single tissue or plasmatic detoxification enzyme, which can lead to some unclear or incomplete information [<xref rid="B15-cells-08-01013" ref-type="bibr">15</xref>]. In the absence of off-target ligands recognized, we have listed some off-target effects that might contribute to the development of innovative therapeutic strategies.</p></sec><sec id="sec3-cells-08-01013"><title>3. Resistance Mechanisms and Signaling Pathways</title><p>Cytotoxic Chemotherapy, at its most simplistic, means the use of chemical compounds to kill cancer cells more effectively than non-tumoral cells [<xref rid="B2-cells-08-01013" ref-type="bibr">2</xref>]. As the knowledge of cancer biology expands, drug development in cancer research could migrate from the discovery of natural compounds to the design of synthetic drug candidates that aim at exclusive or specific cancer targets in what is known as Targeted Therapy [<xref rid="B2-cells-08-01013" ref-type="bibr">2</xref>]. Targeted drug development has become an exciting field for academics and the pharmaceutical industry since imatinib approval in 1995. At the present time, there are twice as many targeted drugs (~120) approved by the FDA than cytotoxic small molecules (~60) (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S1</xref>; Table 2).</p><p>All FDA approved small molecule cytotoxic antineoplastic drugs available as at May 2019 are listed in <xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S1</xref>, and all available targeted antineoplastic agents approved by the FDA up to May 2019 are presented in <xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S2</xref>. </p><p>One of the most appealing differences between Cytotoxic and Targeted Therapy is in the development of specific acquired resistance mechanisms. If ATP-binding cassette (ABC) transporters, enzymatic detoxification, and DNA homeostasis proteins mostly affect cytotoxic drugs, the targeted antineoplastic agents do not. These conclusions can be reached by a close examination of <xref ref-type="app" rid="app1-cells-08-01013">Supplementary Tables S1 and S2</xref>. The summary of the most common specific resistance mechanisms for both cytotoxic and targeted therapies is presented in <xref rid="cells-08-01013-t001" ref-type="table">Table 1</xref>. The signaling pathways associated with resistance to antitumor small molecules and targeted therapies are briefly discussed below.</p></sec><sec id="sec4-cells-08-01013"><title>4. ABC Transporters</title><p>As seen in <xref rid="cells-08-01013-t001" ref-type="table">Table 1</xref>, the main cause of resistance to cytotoxic drugs is the overexpression of ABC transporters in the plasma membrane of cancer cells. Both intrinsic and acquired resistance can be specific to a certain drug, or nonspecific, covering a broad spectrum of drugs. When the spectrum of the resistance is so broad that it covers drugs with unrelated structures and targets in such a way that it is not possible to make a clear association between them, it is called multidrug resistance (MDR). ABC transporters were the first and most studied mechanism of resistance associated with clinical MDR [<xref rid="B16-cells-08-01013" ref-type="bibr">16</xref>,<xref rid="B17-cells-08-01013" ref-type="bibr">17</xref>]. MDR can be understood from either a cellular or a clinical point of view.</p><p>From a cellular perspective, resistance might be a consequence of the low intracellular concentration of the cytotoxic drug. ABC transporters can bind anticancer drugs either from the surroundings of the plasma membrane or intracellular vesicles, and transport them out of the cell directly to the external milieu or through exocytosis [<xref rid="B18-cells-08-01013" ref-type="bibr">18</xref>].</p><p>Clinically, MDR is the main cause of failure in the treatment with cytotoxic drugs [<xref rid="B19-cells-08-01013" ref-type="bibr">19</xref>], which can be explained in part, at least, by the extensive overexpression of several ABC transporters and its long list of substrates among antineoplastic agents (mitomycin, chlorambucil, methotrexate, pemetrexed, 5-fluorouracil, mercaptopurine, estramustine, docetaxel, paclitaxel, vinblastine, vincristine, vinorelbine, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, irinotecan, topotecan, dactinomycin, and etoposide—as seen in <xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S1</xref>). </p><p>For several years, detection and inhibition of a minimum panel of clinically relevant ABC transporters have been attempted [<xref rid="B17-cells-08-01013" ref-type="bibr">17</xref>,<xref rid="B19-cells-08-01013" ref-type="bibr">19</xref>]. However, it is clear that intra-tumor heterogeneity also affects the number of possible combinations of transporters regulated in different subpopulations. Some leukemia cohorts, for example, have shown overexpression of multiple ABC transporters among their patients [<xref rid="B20-cells-08-01013" ref-type="bibr">20</xref>,<xref rid="B21-cells-08-01013" ref-type="bibr">21</xref>,<xref rid="B22-cells-08-01013" ref-type="bibr">22</xref>]. The Cancer Genome Atlas (TCGA) data have also been used to show these expression level discrepancies among patients and cancer types [<xref rid="B17-cells-08-01013" ref-type="bibr">17</xref>].</p><p>The clinical use of ABC transporter inhibitors is long hampered by the severe toxicities presented. Numerous ABC transporter inhibitors have been clinically tested in the last forty years [<xref rid="B17-cells-08-01013" ref-type="bibr">17</xref>,<xref rid="B19-cells-08-01013" ref-type="bibr">19</xref>,<xref rid="B23-cells-08-01013" ref-type="bibr">23</xref>]. Recently, fourth-generation ABC transporter inhibitors have been developed, mostly based on natural and semi-synthetic compounds [<xref rid="B24-cells-08-01013" ref-type="bibr">24</xref>].</p><p>The development of reliable and validated methods for the adequate detection and quantification of ABC transporters is an ongoing challenge [<xref rid="B17-cells-08-01013" ref-type="bibr">17</xref>,<xref rid="B19-cells-08-01013" ref-type="bibr">19</xref>]. Nonetheless, the importance of these transporters in limiting drug delivery, affecting clinical outcomes, and the increased expression of ABC transporters in several cancers, justifies the considerable effort [<xref rid="B19-cells-08-01013" ref-type="bibr">19</xref>]. </p></sec><sec id="sec5-cells-08-01013"><title>5. Enzymatic Detoxification</title><p>The second cause of resistance to cytotoxic drugs is the increased activity or expression of specific detoxification enzymes of each drug (<xref rid="cells-08-01013-t001" ref-type="table">Table 1</xref>). For example, Bleomycin, which can be used for cervical, head and neck, lymphomas, penile, testicular, and vulvar cancer [<xref rid="B25-cells-08-01013" ref-type="bibr">25</xref>], showed bleomycin hydrolase [<xref rid="B26-cells-08-01013" ref-type="bibr">26</xref>,<xref rid="B27-cells-08-01013" ref-type="bibr">27</xref>,<xref rid="B28-cells-08-01013" ref-type="bibr">28</xref>] as a mechanism of detoxification, and the increased activity of bleomycin hydrolase, N-acetylating enzymes, and bleomycin-binding proteins [<xref rid="B27-cells-08-01013" ref-type="bibr">27</xref>,<xref rid="B28-cells-08-01013" ref-type="bibr">28</xref>,<xref rid="B29-cells-08-01013" ref-type="bibr">29</xref>], as mechanisms of resistance (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S1</xref>). </p><p>In addition to specific detoxification enzymes of each drug, glutathione S-transferase (GST) shows a broad detoxification effect. GST participates in the detoxification of several antineoplastic drugs by binding a glutathione molecule to it, therefore promoting some inactivation and increasing the affinity to some ABC transporters, especially from ABCC and ABCG families [<xref rid="B30-cells-08-01013" ref-type="bibr">30</xref>,<xref rid="B31-cells-08-01013" ref-type="bibr">31</xref>,<xref rid="B32-cells-08-01013" ref-type="bibr">32</xref>].</p></sec><sec id="sec6-cells-08-01013"><title>6. DNA Homeostasis-Related Signaling Pathways and Cytoskeletal Disruptors</title><p>In addition to increased activity of detoxification, mutations, overexpression, and downregulation of key targets, namely topoisomerase I and tubulin isoforms, are the next most common alterations. These are alterations that affect two major families, the topoisomerase inhibitors and cytoskeletal disruptors, which are among the most used cytotoxic drugs. Tubulin directly participates in the formation of the metaphase spindle and separation of sister chromatids, and when this is not adequately completed, leads to cell death by mitotic catastrophe [<xref rid="B33-cells-08-01013" ref-type="bibr">33</xref>,<xref rid="B34-cells-08-01013" ref-type="bibr">34</xref>]. Changes in isotype expression [<xref rid="B35-cells-08-01013" ref-type="bibr">35</xref>], mutations in [<xref rid="B35-cells-08-01013" ref-type="bibr">35</xref>,<xref rid="B36-cells-08-01013" ref-type="bibr">36</xref>,<xref rid="B37-cells-08-01013" ref-type="bibr">37</xref>] and/or overexpression of tubulins [<xref rid="B35-cells-08-01013" ref-type="bibr">35</xref>], and post-translational modifications of tubulins have been observed in many cancers [<xref rid="B38-cells-08-01013" ref-type="bibr">38</xref>].</p><p>Since most cytotoxic drugs are genotoxic, it is not surprising to have proteins associated with DNA homeostasis among the most common resistance mechanisms (<xref rid="cells-08-01013-t001" ref-type="table">Table 1</xref>). Therefore, several common resistance mechanisms in response to cytotoxic drugs are associated with DNA homeostasis (topoisomerases, tubulin, dCK, NF-κB, MGMT, ALDH1, and TP53). These molecular pathways are crucial key points to cytotoxic treatment resistance and will be discussed briefly.</p><p>Topoisomerases are vital regulators of DNA topology during DNA replication, transcription, repair, and recombination. Type I or II topoisomerases produce reversible single- or double-strand breaks, respectively. Their current pharmacological inactivation is related to stalled replication fork and cytotoxic DNA fragmentation by the formation of irreparable covalently bound DNA–protein–drug ternary complexes. Several other classes of topoisomerase inhibitors are under development, but none have presented tolerable toxicity, acceptable specificity, and potency with proper pharmacokinetics [<xref rid="B39-cells-08-01013" ref-type="bibr">39</xref>,<xref rid="B40-cells-08-01013" ref-type="bibr">40</xref>]. </p><p>dCK is a key enzyme, usually the rate-limiting one in the synthesis of deoxynucleosides in the salvage pathway, a crucial alternative compensatory pathway for deoxynucleotide synthesis when the de novo pathway is inhibited or downregulated [<xref rid="B41-cells-08-01013" ref-type="bibr">41</xref>,<xref rid="B42-cells-08-01013" ref-type="bibr">42</xref>]. dCK overexpression is a key component to resistance to nucleoside analogs (cladribine, clofarabine, cytarabine, decitabine, gemcitabine, nelarabine) (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S1</xref>). </p><p>Increased DNA methyltransferase (MGMT) protein levels are one of the most important mechanisms of resistance to alkylating agents because it can repair the cytotoxic O6-methylguanine DNA adduct and prevent its harmful effects, which affect therapy efficiency [<xref rid="B43-cells-08-01013" ref-type="bibr">43</xref>]. For example, when tumors showed methylation on the MGMT promoter, glioblastoma patients treated with the alkylating agent temozolomide and radiotherapy showed 21.7 months of median survival, compared to only 15.3 months among those who were assigned to radiotherapy only. In the absence of methylation of the MGMT promoter, there is no statistical difference in survival between the treatment groups, regardless of temozolomide treatment [<xref rid="B44-cells-08-01013" ref-type="bibr">44</xref>]. This suggested that patients with wild type MGMT have nearly no response to the alkylating agent. One may speculate that increasing the methylation status might have some benefit to enhance the cell death response induced by alkylating agent treatment in glioblastomas. After DNA damage, tumor suppressor TP53 is induced to regulate cell cycle arrest, DNA repair, and apoptotic cell death. Deletions, nonsense, and frameshift mutations that lead to its loss-of-function are common across a vast range of cancer cell type tumorigenesis. Gain-of-function oncogenic mutations are also common and represent a different mechanism for which <italic>TP53</italic> can participate in tumorigenesis. When these oncogenic mutations are present in cancer, <italic>TP53</italic> expression is usually associated with a more aggressive form of the disease, with increased tumor genome instability and metastatic potential (recently reviewed in [<xref rid="B45-cells-08-01013" ref-type="bibr">45</xref>]). Altogether, <italic>TP53</italic> mutations are found in nearly 50% of human cancers, and they are one of the classically associated resistance mechanisms against cytotoxic therapy.</p></sec><sec id="sec7-cells-08-01013"><title>7. Activation of NF-κB</title><p>NF-κB is a small family of five proteins with two effector transcription factor complexes, p65–p50, and p52-RelB [<xref rid="B46-cells-08-01013" ref-type="bibr">46</xref>]. These complexes are respectively associated with the canonical and non-canonical signaling pathways. The canonical pathway is activated under the control of cell receptors to several pro-inflammatory cytokines, tumor necrosis factor (TNF), lipid polysaccharides, growth factors, and antigens, whereas, the non-canonical pathway is triggered by Lymphotoxin beta receptor (LTBR), cluster of differentiation 40 (CD40), B-cell activating factor receptor 3 (BR3), and RANK. Both pathways are limited by the initial participation of cytosolic inactivating complexes. The canonical pathway involves the IKB and IKK inhibitory proteins, and the non-canonical recruit only IKK proteins. The activation of the receptors for these pathways triggers a sequence of specific phosphorylations and ubiquitinations that rapidly and transiently release the active form of their respective transcription factor complexes, which translocate to the nucleus where they effectively activate hundreds of validated transcriptional targets [<xref rid="B46-cells-08-01013" ref-type="bibr">46</xref>]. Because of the huge plethora of target genes and our poor understanding of this complex orchestra, most clinically approved inhibitors have an incomplete description of their mechanisms of action. The NF-κB pathway participates in cellular immunity, inflammation, apoptosis, cell differentiation, proliferation, and response to stress. In cancer, activation of NF-κB rescues the cell from the apoptotic pathway, promoting its survival, preventing cell death, and promoting proliferation [<xref rid="B46-cells-08-01013" ref-type="bibr">46</xref>]. </p></sec><sec id="sec8-cells-08-01013"><title>8. Increased Levels of ALDH1</title><p>Several types of cancer stem cell (CSC) populations have elevated aldehyde dehydrogenase activity (ALDH), which converts toxic aldehydes into carboxylic acids [<xref rid="B47-cells-08-01013" ref-type="bibr">47</xref>]. ALDH enzymatic activity supports cancer stem cell self-renewal, protection against oxidative stress, and participation in energetic metabolism as a reliable alternative source of nicotinamide adenine dinucleotide (NADH), a convenient substrate for ATP synthesis. They also confer resistance to selected anticancer agents by metabolic inactivation and have been implicated in every tumorigenic process, from initiation to metastasis [<xref rid="B48-cells-08-01013" ref-type="bibr">48</xref>,<xref rid="B49-cells-08-01013" ref-type="bibr">49</xref>]. Therefore, it is not surprising that an increased level of ALDH is one of the specific resistance mechanisms associated with cytotoxic therapy.</p></sec><sec id="sec9-cells-08-01013"><title>9. Signaling Pathways Associated with Targeted Therapies</title><p>Differently from cytotoxic drugs, the resistance mechanisms of target therapy are mostly specific key alterations in their signaling pathway targets, such as mitogen-activated protein kinase (MAPK) pathway (also known as RAS-RAF-MEK-ERK pathway), phosphoinositide 3-kinase pathway (PI3K-AKT-mTOR), epidermal growth factor (EGF), EGF receptor (EGFR), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), insulin-like growth factors (IGFs), key regulators of apoptosis B-cell lymphoma 2 (BCL2) family, fibroblast growth factors (FGFs), and signal transducers and activators of transcription (STATs). Except for the overexpression of ABC transporters, which occurs but with less frequency than for cytotoxic drugs, the major mechanism of action of targeted therapy is key alterations in their specific signaling pathway targets (<xref rid="cells-08-01013-t001" ref-type="table">Table 1</xref>). Briefly, these signaling pathways can be associated with Survival (PI3K, AKT, mTOR, STAT), Proliferation (MAPK, STAT, growth factors—FGFs, EGFR, IGFs), and Cell Death (BCL2 family and PTEN).</p><p>Therefore, the initial excitement surrounding targeted therapy might be diminished by the nature of the therapy itself. From one perspective, single-agent targeted therapy inhibits specific dysregulated pathways. Such treatment would represent a strong but punctual selective pressure over cancer cell populations [<xref rid="B50-cells-08-01013" ref-type="bibr">50</xref>]. The strong specificity allows reduced toxicity and promotes efficient clinical response for those patients who might benefit from the treatment. On the other hand, targeted therapy is also largely limited by this strong specificity in the face of the multiple alterations cancer cells present [<xref rid="B6-cells-08-01013" ref-type="bibr">6</xref>], and which are necessary to circumvent the redundant signaling pathways that prevent tumorigenesis [<xref rid="B51-cells-08-01013" ref-type="bibr">51</xref>]. The efficacy of the therapy is also hampered by the large intra- and inter-tumor heterogeneity [<xref rid="B52-cells-08-01013" ref-type="bibr">52</xref>]. These limitations might be seen by the relatively small benefit some patients present from the intended targeted therapy and by the relative transient remission, accompanied by relapse, which is often and usually together with acquired resistance [<xref rid="B53-cells-08-01013" ref-type="bibr">53</xref>]. All these points have been the theme of some nice discussions in recent works [<xref rid="B50-cells-08-01013" ref-type="bibr">50</xref>,<xref rid="B54-cells-08-01013" ref-type="bibr">54</xref>,<xref rid="B55-cells-08-01013" ref-type="bibr">55</xref>,<xref rid="B56-cells-08-01013" ref-type="bibr">56</xref>].</p><p>One key aspect to circumvent the emergence of resistance might be to “spread” the selective pressure made by antineoplastic treatment attacking multiple pathways simultaneously, possibly by the combination of multiple drugs [<xref rid="B19-cells-08-01013" ref-type="bibr">19</xref>,<xref rid="B56-cells-08-01013" ref-type="bibr">56</xref>]. This must be performed according to already established guidelines such as (i) each single agent should be effective in monotherapy; (ii) use agents with different mechanisms of action, preferably on different subcellular structures and/or different phases of the cell cycle; (iii) avoid overlapping toxicities, particularly over vital organs or with life-threatening side effects; (iv) optimize dose and schedule of treatment and intervals to improve both efficacy and minimize toxicities; and, finally, (v) have a clear understanding of the mechanism of interaction among drugs [<xref rid="B57-cells-08-01013" ref-type="bibr">57</xref>,<xref rid="B58-cells-08-01013" ref-type="bibr">58</xref>,<xref rid="B59-cells-08-01013" ref-type="bibr">59</xref>,<xref rid="B60-cells-08-01013" ref-type="bibr">60</xref>]. The last of these is particularly poorly understood. This statement is supported by a relatively recent study [<xref rid="B12-cells-08-01013" ref-type="bibr">12</xref>]. </p></sec><sec id="sec10-cells-08-01013"><title>10. Resistance Mechanisms can be Associated with the Hallmarks of Cancer Cells</title><p>When resistance mechanisms and signaling pathways are associated with specific hallmarks of cancer, it became evident that some hallmarks are mostly associated with oncogenes (genome instability, survival, proliferation, angiogenesis); meanwhile, others are almost tumor suppressor exclusives (evasion of inhibitory factors, cell death). Classic oncogene alterations are associated with gain-of-function in which one single genetic alteration is enough to over-activate the oncogenic signaling pathway; meanwhile, two-hit tumor suppressors are often associated with inactivating mutations and downregulation of key signaling elements of the pathway. It seems that the two-hit requirements for an effective intervention on a tumor suppressor pathway have limited the development of tumor suppressor-based therapies since most targeted therapies are aimed at oncogenes (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S2</xref>).</p><p>Cytotoxic and targeted therapies increased detoxification and specific signaling pathway mechanisms, respectively. Interestingly, both mechanisms can be associated with the hallmarks of cancer cells. Whereas increased detoxification mechanisms can be associated with altered metabolism of cancer cells, the signaling pathways induced by target therapy as resistance mechanisms can be associated with all the hallmarks. In <xref rid="cells-08-01013-t002" ref-type="table">Table 2</xref>, there is an association between the specific resistance mechanisms listed in <xref ref-type="app" rid="app1-cells-08-01013">Supplementary Tables S1 and S2</xref> and the most affected signaling pathways in cancer cells, as well as their corresponding hallmarks of cancer. </p><p>Some cellular proteins and processes are major regulators of cell homeostasis, which make them largely associated with several, if not all, hallmarks. Some examples are NF-κB [<xref rid="B46-cells-08-01013" ref-type="bibr">46</xref>], PTEN [<xref rid="B61-cells-08-01013" ref-type="bibr">61</xref>], and autophagy [<xref rid="B62-cells-08-01013" ref-type="bibr">62</xref>,<xref rid="B63-cells-08-01013" ref-type="bibr">63</xref>]. NF-κB was briefly mentioned above.</p></sec><sec id="sec11-cells-08-01013"><title>11. Signaling Pathways Related to the Hallmark Evasion of Growth Suppression</title><p>PTEN is one of the most commonly affected tumor suppressors proteins during tumorigenesis [<xref rid="B64-cells-08-01013" ref-type="bibr">64</xref>]. Its gene encodes a tumor suppressor phosphatase protein that physiologically prevents the entry to the cell cycle, as well as G2/M transition and mitosis. Regulation of the cell cycle by PTEN has been recently reviewed elsewhere [<xref rid="B65-cells-08-01013" ref-type="bibr">65</xref>]. PTEN arrests cells at G1 by inactivating the PI3K/AKT pathway, thus inhibiting cell cycle progression through the regulation of several signaling molecules, including decreased levels of cyclin D and inactivation by phosphorylation of the retinoblastoma protein (RB). RB regulates the restriction point, the G1-late stage when cells become committed to proliferate [<xref rid="B66-cells-08-01013" ref-type="bibr">66</xref>]. Cell cycle progression relies on the phosphorylated state of RB, which is tightly controlled by cyclin-dependent kinases (CDKs).</p><p>Upon mitogenic stimulation, cyclin D-CDK4/CDK6 phosphorylates RB, thereby inactivating it and promoting the release of transcription factors of the E2F family, which activate the transcription of target genes required for cell cycle progression [<xref rid="B67-cells-08-01013" ref-type="bibr">67</xref>]. Dysregulation of this canonical RB function is central in cancer, with components of the CDK4/6-RB pathway often displaying mutations that will result in sustained cell proliferation; for instance, in tumors that retain RB expression, uncontrolled cell cycle activity may be due to the amplification of the cyclin D1 gene (<italic>CCND1</italic>) and <italic>CDK4</italic>, activating <italic>CDK4/6</italic> mutations or silencing of CDK inhibitors (CKI) [<xref rid="B67-cells-08-01013" ref-type="bibr">67</xref>,<xref rid="B68-cells-08-01013" ref-type="bibr">68</xref>].</p><p>There are 13 members of the CDK family, from which only four—CDK1, CDK2, CDK4, and CDK6—are direct regulators of the cell cycle [<xref rid="B69-cells-08-01013" ref-type="bibr">69</xref>]. <italic>CDK4</italic> and <italic>CDK6</italic> have been implicated as drivers of oncogenesis in several cancers [<xref rid="B70-cells-08-01013" ref-type="bibr">70</xref>] for more than 20 years.</p><p>There are two major families of physiological CKI that regulate the cell cycle through cyclin-CDK activity in animals: INK4 and CIP/KIP families. They are both allosteric inhibitors of CDKs [<xref rid="B71-cells-08-01013" ref-type="bibr">71</xref>].</p><p>RB is also regulated by phosphorylation. It has been recently proposed that in a non-cycling cell, when RB is in its “active” form sequestering E2F family members, there are multiple mono-phosphorylated isoforms of RB (mP-RB) simultaneously present [<xref rid="B72-cells-08-01013" ref-type="bibr">72</xref>]. The authors showed functional differences between mP-RBs beyond the regulation of the cell cycle machinery. It is yet unknown which proteins participate in the complexes to each type of mP-RBs, which proteins are regulated by each isoform, in which situations these isoforms are selectively regulated, which isoforms are functionally distinct or redundant, and so on. There is also evidence for hypo- and hyper-phosphorylated isoforms, which have been largely studied by other groups [<xref rid="B73-cells-08-01013" ref-type="bibr">73</xref>,<xref rid="B74-cells-08-01013" ref-type="bibr">74</xref>].</p></sec><sec id="sec12-cells-08-01013"><title>12. CDK Inhibitors</title><p>Pharmacological specific inhibition of CDKs has been long pursued. The most promising early CDK inhibitor was the pan-inhibitor CDK flavopiridol (or alvocidib) [<xref rid="B72-cells-08-01013" ref-type="bibr">72</xref>,<xref rid="B75-cells-08-01013" ref-type="bibr">75</xref>,<xref rid="B76-cells-08-01013" ref-type="bibr">76</xref>,<xref rid="B77-cells-08-01013" ref-type="bibr">77</xref>]. Flavopiridol was tested in more than 60 clinical trials for 15 years, mostly with disappointing degrees of antitumor activity [<xref rid="B76-cells-08-01013" ref-type="bibr">76</xref>,<xref rid="B78-cells-08-01013" ref-type="bibr">78</xref>]. Flavopiridol did not obtain approval, which was attributed to limited clinical efficacy [<xref rid="B79-cells-08-01013" ref-type="bibr">79</xref>,<xref rid="B80-cells-08-01013" ref-type="bibr">80</xref>,<xref rid="B81-cells-08-01013" ref-type="bibr">81</xref>,<xref rid="B82-cells-08-01013" ref-type="bibr">82</xref>] and severe toxicities [<xref rid="B80-cells-08-01013" ref-type="bibr">80</xref>,<xref rid="B82-cells-08-01013" ref-type="bibr">82</xref>].</p><p>Selective CDK4/6 inhibitor compounds were developed, clinically tested, and recently approved for human use, namely, palbociclib (PD0332991, Pfizer, NY, USA), ribociblib (LEE011, Novartis, Basel, Switzerland) and abemaciclib (LY2835219, Eli Lilly, Indianapolis, USA). These specific CDK have raised much attention and excitement since their first approvals. Palbociclib was the first to receive its approval. It was indicated for first-line use among post-menopausal women with advanced hormone positive HER2 negative breast cancer who have not been previously treated with systemic chemotherapy [<xref rid="B83-cells-08-01013" ref-type="bibr">83</xref>]. In April 2019, its approval was also extended for the treatment of men with hormone positive HER2 negative metastatic breast cancer [<xref rid="B84-cells-08-01013" ref-type="bibr">84</xref>].</p><p>Recent reviews of the clinical trials with these selective CDK4/6 inhibitors and their impact on clinical outcomes have discussed great advances in median progression-free survival, and objective response ratio among hormone receptor positive breast cancer patients treated with all three approved CDK [<xref rid="B85-cells-08-01013" ref-type="bibr">85</xref>,<xref rid="B86-cells-08-01013" ref-type="bibr">86</xref>].</p><p>There are some similarities between the approvals of palbociclib [<xref rid="B83-cells-08-01013" ref-type="bibr">83</xref>], ribociclib [<xref rid="B87-cells-08-01013" ref-type="bibr">87</xref>], and abemaciclib [<xref rid="B88-cells-08-01013" ref-type="bibr">88</xref>] for breast cancer treatment. All three drugs were first approved for advanced hormone positive HER2 negative breast cancer patients in combination with hormone therapy (letrozole with palbociclib or ribociclib, and fulvestrant/abemaciclib), for which they presented synergistic growth inhibitory activity. The approvals were granted based mostly on progression-free survival and objective response ratio, without data on overall survival. The larger cohort among the three trials enrolled 165 women, a small cohort for survival purposes. Moreover, the three approvals are upfront treatments aiming mostly at disease control before systemic chemotherapy is given, which, although more aggressive, is also a more established curative approach.</p><p>The full potential of selective CDK is under investigation in many preclinical and clinical studies [<xref rid="B85-cells-08-01013" ref-type="bibr">85</xref>]. As target therapies, CDK treatment produces some specific resistances. Overcoming these predictive resistances might greatly improve clinical outcomes as recently discussed elsewhere [<xref rid="B89-cells-08-01013" ref-type="bibr">89</xref>].</p><p>Preclinical and clinical data support the notion that the rational treatment with cell cycle phase-specific antitumor agents might produce synergic cytotoxic effects depending on the choice and order of drugs to be administered. For example, sequential administration of CDK followed by DNA damaging cell cycle specific agents have been tested in a panel of TP53 mutant and wild-type breast and human colorectal cancer cell lines. The authors used roscovitine, a purine-based nonselective CDK, followed by doxorubicin [<xref rid="B90-cells-08-01013" ref-type="bibr">90</xref>]. The CDK inhibition increased apoptosis induced by doxorubicin only on TP53 null or mutant cell lines, highlighting the ability of wild type TP53 to prevent cell cycle synthetic lethality due to DNA damaging agents. The authors also reported superior benefits in terms of overall survival and decreased proliferation in human breast cancer xenografts treated with the sequential regime of roscovitine followed by doxorubicin over the concomitant combination (<italic>p</italic> < 0.0001) or either drug alone (<italic>p</italic> < 0.01) [<xref rid="B90-cells-08-01013" ref-type="bibr">90</xref>]. It is worth testing similar types of experiments with CDK4/6 selective inhibitors.</p></sec><sec id="sec13-cells-08-01013"><title>13. Signaling Pathways Related to Cell Death</title><p>In addition to sustained proliferation and evasion of growth suppression, resistance to cell death is one of the three pivotal drivers of tumorigenesis [<xref rid="B91-cells-08-01013" ref-type="bibr">91</xref>]. From analyzing <xref rid="cells-08-01013-t002" ref-type="table">Table 2</xref>, one can promptly realize that many of the same signaling disruptions are exploited by cancer cells and allow resistance to anticancer therapy. Importantly, programmed cell death (PCD), triggered by several external and internal stress signals, must be overcome if both tumorigenesis and drug resistance are to be successful. The best-characterized form of PCD is apoptosis, which is composed by two pathways—one activated by death receptor signaling and the other by intracellular, mitochondrial signaling—that converge at the level of effector proteases called caspases. These will execute an extensive intracellular proteolytic program, leading to apoptotic cell death. Disruptions in the mitochondrial (or “intrinsic”) apoptotic program are widely involved in cancer progression and therapy resistance [<xref rid="B91-cells-08-01013" ref-type="bibr">91</xref>]. The ultimate trigger to caspase activation in the intrinsic program is the release of mitochondrial factors, such as cytochrome c, through mitochondrial outer membrane permeabilization (MOMP). This process is tightly regulated by a dynamic balance among the members of the BCL2 protein family at the outer mitochondrial membrane (OMM): the pro-apoptotic BCL2 proteins, Bax and Bak, directly promote MOMP by forming pores at the OMM, which are usually inhibited by binding of the anti-apoptotic (e.g., BCL2, BCL2-like protein 1, and MCL1/BCL2L3) BCL2 proteins [<xref rid="B92-cells-08-01013" ref-type="bibr">92</xref>]. Additionally, BH3-only proteins (e.g., Bid, Bad, Bim, Noxa, and Puma) directly inhibit anti-apoptotic BCL2 proteins and/or directly activate Bax/Bak, thus inducing MOMP and triggering caspase activation. When activated, the tumor suppressor TP53, best known for its surveillance activity regarding DNA damage, promotes the expression of several genes regulating the intrinsic pathway, mainly <italic>Bax</italic> and <italic>PUMA</italic>, ultimately also leading to caspase activation [<xref rid="B93-cells-08-01013" ref-type="bibr">93</xref>]. Perhaps unsurprisingly, mutations leading to enhanced anti-apoptotic BCL2 signaling, downregulation of Bax and Bak, and p53 inactivation, promote drug resistance across many cancer types (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Tables S1 and S2</xref>).</p></sec><sec id="sec14-cells-08-01013"><title>14. Induction of Autophagy is a Common Cellular Phenomenon associated with Cell Death Resistance</title><p>Autophagy is an evolutionarily conserved process of elimination and recycling “damaged” or “old” cytoplasmic cell components, structures, and organelles in lysosomes [<xref rid="B94-cells-08-01013" ref-type="bibr">94</xref>]. Autophagy has been recently associated with several hallmarks of cancer [<xref rid="B63-cells-08-01013" ref-type="bibr">63</xref>]: sustained proliferation (energetic source); promotion of epithelial–mesenchymal transition; sustained survival during cell migration (evasion of anoikic cell death) and metastasis (facilitates tumor cell dormancy and quiescence, survival and proliferation during new tumor formation); pro-survival alternative energetic source of dysregulated aerobic metabolism; evasion of cell death (evasion of apoptosis, survival of residual cancer stem cells after chemotherapy); and, genome instability (sustains DNA damage repair system) [<xref rid="B95-cells-08-01013" ref-type="bibr">95</xref>,<xref rid="B96-cells-08-01013" ref-type="bibr">96</xref>].</p><p>Physiologically, basal autophagy is a recycling energetic system for the turnover of proteins and lipids, which might be increasingly activated in response to a stressor, like starvation. Therefore, it might be seen as a pro-survival process for any normal or cancerous cells. Under prolonged periods of starvation, a regulated programmed cell death (PCD) process known as autophagic cell death is observed [<xref rid="B97-cells-08-01013" ref-type="bibr">97</xref>]. As briefly discussed above, there are many possible opportunities for cancer therapy based on pharmacological modulation of autophagy and to promote increased cancer cell death. We can and should take advantage of these phenomena [<xref rid="B98-cells-08-01013" ref-type="bibr">98</xref>,<xref rid="B99-cells-08-01013" ref-type="bibr">99</xref>].</p><p>Autophagy plays its role in cancer by regulating several pathways which rule over cell life and death, such as BCL2, Class III and I PI3K (PI3K-I and PI3K-III), AKT, mTORC ½, and TP53 [<xref rid="B100-cells-08-01013" ref-type="bibr">100</xref>]. Despite the complexity of the mTOR signaling network, mTORC1 is a well-defined central autophagy inhibitor, acting as a point of convergence for many pathways: the pro-survival PI3K-I-AKT and MAPK pathways induce mTORC1, whereas AMP-activated protein kinase (AMPK) signaling inhibits it [<xref rid="B101-cells-08-01013" ref-type="bibr">101</xref>]. mTORC1 signaling is also induced by growth factors via the PI3K-I-AKT and MAPK pathways.</p><p>Furthermore, TP53 also presents a “Janus role” of its own in autophagy, both inducing (cytoplasmic p53) and inhibiting (nuclear p53, through AMPK) mTORC1 activity. Autophagy induction and enhanced PI3K-AKT-mTOR and MAPK signaling pathways are often related to resistance against a wide range of drugs in several cancer types, which is further evidence of its importance during tumorigenesis (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S2</xref> and <xref rid="cells-08-01013-t002" ref-type="table">Table 2</xref>). Furthermore, it is important to have in mind the significant cross-talk between autophagy and apoptosis signaling [<xref rid="B102-cells-08-01013" ref-type="bibr">102</xref>]: As well as inhibiting autophagy, growth factor signaling, for example, it will also induce the JAK/STAT1/3 pathway, which will, in turn, induce anti-apoptotic BCL2 signaling.</p><p>The very nature of the network connection of the major signaling pathways, both affected during the initial tumorigenic process and therapy-induced, is very complex. The complexity is not only due to many connection points, but also because they affect various cellular processes related to all hallmarks of cancers. This sophistication makes the topic interesting and intriguing, as can be seen in <xref ref-type="fig" rid="cells-08-01013-f001">Figure 1</xref>, where cell signaling is summarized according to cancer markers.</p><p>Another level of the additional complexity of the signaling network is evidenced by the fact that proteins can show multiple roles in the cell. For example, RB and β-catenin, both known to be involved in proliferation, have been described by regulating cell death according to the context of tumor cells [<xref rid="B103-cells-08-01013" ref-type="bibr">103</xref>,<xref rid="B104-cells-08-01013" ref-type="bibr">104</xref>].</p></sec><sec id="sec15-cells-08-01013"><title>15. Clinical Trials with Combination Regimens Containing Inhibitors of Signaling Pathways Related to Drug Resistance</title><p>The concept of increased cell death by blocking the resistance mechanisms that protect cancer cells against systemic chemotherapy is relatively simple and intuitive. Similarly, increased cell death is to be expected when combining anticancer drugs in a cocktail in which one of its drugs might act as an inhibitor of the signaling pathways related to the known resistance mechanisms against one or some other anticancer drugs in combination. The general simplest idea of combining cytotoxic and targeted chemotherapy is usually attributed for target therapy somehow sensitizing cells to increased cytotoxicity (<xref rid="cells-08-01013-t003" ref-type="table">Table 3</xref>). Meanwhile, the rationale for combining two targeted drugs might be much more variable and require a case-by-case evaluation (<xref rid="cells-08-01013-t004" ref-type="table">Table 4</xref>). Most combination studies between targeted therapies do not aim at the resistance mechanisms affected by the drugs in the combination. We have only found five examples that fit into this strategy. We searched among already registered clinical trials for examples of drug combinations in which a specific targeted drug might inhibit the signaling pathway-related to the resistance to the second targeted combined drug (<xref rid="cells-08-01013-t004" ref-type="table">Table 4</xref>). With this rationale, we found five ongoing phase I, six ongoing phase II, three phase I completed, and two phase II completed (<xref rid="cells-08-01013-t004" ref-type="table">Table 4</xref>).</p><p>Several clinical trials that investigate mechanism-based targeted drug combinations are ongoing. They present a rationale for dual inhibition of one or more pathways that could increase cell death (<xref rid="cells-08-01013-t004" ref-type="table">Table 4</xref>). Some combinations represent a dual blockade in pathways related to different hallmarks of cancer (<xref ref-type="fig" rid="cells-08-01013-f001">Figure 1</xref>), such as the combination of bevacizumab and erlotinib for advanced liver cancer, which targets both tumor neovascularization and proliferative signaling (EGFR and vascular endothelial growth factor dual blockade, <xref rid="cells-08-01013-t004" ref-type="table">Table 4</xref>).</p><p>Another example of mechanism-based targeted drug combinations is ongoing for pancreatic tumors. Since the enhanced PI3K/mTOR activity confers CDK4/6 inhibitor resistance therapy, the inhibition of those pathways should be tested (<xref rid="cells-08-01013-t004" ref-type="table">Table 4</xref>). This is an interesting ongoing clinical trial that is currently evaluating the combination of ribociclib, a CDK4/6 inhibitor, and everolimus, an mTOR inhibitor in metastatic pancreatic adenocarcinoma patients refractory to 5-fluorouracil (5-FU) and gemcitabine-based chemotherapy [<xref rid="B105-cells-08-01013" ref-type="bibr">105</xref>]. Their cancers have either intrinsic or acquired resistances to first and second lines of treatment. The antiproliferative combination might synergize to increase cell death, which would be unlikely to happen with either targeted therapies alone. mTOR is one of the potent resistance mechanisms against CDK inhibitors (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S2</xref>). Its inhibition with everolimus is a strategy for inhibition of the cross-talk between the pro-survival PI3K-AKT-mTOR pathway and the proliferative RAS–RAF–MEK–ERK signaling pathway. This rationale has already presented some nice results in breast [<xref rid="B106-cells-08-01013" ref-type="bibr">106</xref>] and prostate cancers [<xref rid="B107-cells-08-01013" ref-type="bibr">107</xref>].</p><p>The dual-hit inhibition strategy has some proven benefits over single pathway inhibitors. Some dual hit combinations have been approved for different pathways and cancer types, such as dual inhibition of EGFR, HER2, and MAPK. These combinations trigger specific but distinct mechanisms of resistance. In EGFR and HER-2, for example, improved efficacy is seen without added or more severe toxicities [<xref rid="B108-cells-08-01013" ref-type="bibr">108</xref>]. </p></sec><sec id="sec16-cells-08-01013"><title>16. Intrinsic Toxicity and Compensatory Mechanism of Inhibitors of Key Signaling Pathways of the Resistance Mechanisms </title><p>Many inhibitors of key signaling pathways of the resistance mechanisms can show high toxicity and compensatory mechanisms, as well as several potential targets of the same pathways. For example, somatic alterations in the MAPK pathway that are highly prevalent in human cancer and are also related to therapy resistance, show a wide range of targeted inhibitions (see <xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S2</xref> and <xref rid="cells-08-01013-t001" ref-type="table">Table 1</xref>). Currently, there are no rat sarcoma protein (RAS) inhibitors available, but monotherapy of downstream selective MAPK inhibitors shows great promise, with some examples of already approved regimens. </p><p>Selective monotherapy with rapidly accelerated fibrosarcoma (RAF) inhibitors has greatly improved clinical progress in melanoma patients [<xref rid="B168-cells-08-01013" ref-type="bibr">168</xref>]. However, intra-pathway resistance mechanisms still arise, often related to RAF-independent extracellular signal–regulated kinases (ERK) activation. In this context, v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, dabrafenib therapy has triggered rapidly-growing skin tumors, which can be partially mitigated by combination with trametinib, a mitogen-activated protein kinase kinase (MEK) inhibitor [<xref rid="B169-cells-08-01013" ref-type="bibr">169</xref>]. This downstream inhibition of the pathway reduces possibilities for ERK reactivation. As of May 2019, the FDA has approved a total of three BRAF/MEK combination regimens, with the dabrafenib and trametinib combination being indicated for the treatment of BRAF-V600-positive melanoma, non-small cell lung cancer and anaplastic thyroid cancer (<xref rid="cells-08-01013-t004" ref-type="table">Table 4</xref>). </p><p>There are other inhibition strategies targeting MAPK that aim to offer improved therapy. Early clinical studies of RAF/MEK inhibition combined with immunotherapy, for example, have faced interruption or patient discontinuation due to severe life-threatening toxicities [<xref rid="B170-cells-08-01013" ref-type="bibr">170</xref>], with evidence suggesting that the combination potentiates adverse effects of both strategies when used alone. Larger studies are expected to better define this strategy. This highlights the importance of avoiding accumulated overlapping toxicity in the rationale of the combination to be tested in trials, as seen with other targeted pathways. Importantly, while there are no FDA-approved selective ERK inhibitors, preclinical studies have already shown that ERK mutations and expression imbalances might arise as resistance mechanisms [<xref rid="B171-cells-08-01013" ref-type="bibr">171</xref>]. Recent clinical data suggest that ERK inhibitors therapy-related toxicities are not severe, which opens the possibility for combinations with upstream RAF/MEK inhibition and greater clinical success for the future of MAPK inhibition therapy [<xref rid="B172-cells-08-01013" ref-type="bibr">172</xref>].</p><p>The PI3K-AKT-mTOR pathway is one of the most frequently dysregulated pathways, not only in tumor development but as the mechanism of resistance after treatment (<xref rid="cells-08-01013-t001" ref-type="table">Table 1</xref>). Approximately 50 compounds targeting some of its key proteins have been in clinical development over the years [<xref rid="B173-cells-08-01013" ref-type="bibr">173</xref>]. Although these compounds have reached different stages of clinical trials, a promising response has not been observed as with other approved targeted therapies [<xref rid="B174-cells-08-01013" ref-type="bibr">174</xref>]. For a number of reasons, including high toxicity, only a few PI3K-AKT-mTOR pathway inhibitors have been approved by the FDA and indicated for cancer treatment: four PI3K inhibitors—idelalisib, copanlisib and, more recently, duvelisib and alpelisib (September 2018 and May 2019, respectively); one AKT inhibitor—miltefosine; and, two mTOR inhibitors—temsirolimus and everolimus. </p><p>Inhibition of this signaling pathway has proven to be a double-edged sword between potency and toxicity. Anti-PI3K and anti-mTOR monotherapies, although well-tolerated, have shown only modest efficacy in several clinical trials [<xref rid="B173-cells-08-01013" ref-type="bibr">173</xref>]. On the other hand, combination therapies targeting multiple PI3K-AKT-mTOR components are usually more effective but lead to a build-up of dose-limiting toxicities [<xref rid="B173-cells-08-01013" ref-type="bibr">173</xref>]. Most severe toxicities related to PI3K inhibitors might be explained by severe immune modulations in several organs. Many reviews have recently addressed this complex problem [<xref rid="B175-cells-08-01013" ref-type="bibr">175</xref>].</p><p>Generally, preclinical studies have shown that isoform-specific targeting of PI3K has better therapeutic efficacy and toxicity profiles than pan-inhibitors [<xref rid="B174-cells-08-01013" ref-type="bibr">174</xref>]. The same is true for direct AKT inhibition. Most AKT inhibitors in clinical development are pan-inhibitors, with many clinical trials suspended due to severe hyperglycemia [<xref rid="B176-cells-08-01013" ref-type="bibr">176</xref>]. The efficacy of the AKT inhibitors TCN, TCN-P, and edelfosine is limited due to their toxicity [<xref rid="B177-cells-08-01013" ref-type="bibr">177</xref>]. Miltefosine was the only AKT inhibitor approved by the FDA in 2014, indicated for visceral, cutaneous, and mucosal leishmaniasis. In cancer, miltefosine has limited use mainly due to its gastrointestinal and hemolytic toxicities. Therefore, it has been used as a topical formulation to treat cutaneous lesions caused by lymphoma and cutaneous breast cancer metastasis [<xref rid="B178-cells-08-01013" ref-type="bibr">178</xref>]. Given the central role of AKT signaling dysregulation in cancer, the development of safer AKT inhibitors is urgent.</p><p>Regarding mTOR inhibition, hematologic toxicities of various types were observed in the clinical trials that resulted in FDA approval of temsirolimus: 94% had hemoglobinemia, 53% had lymphocytopenia, 19% had neutropenia, and 40% had thrombocytopenia [<xref rid="B179-cells-08-01013" ref-type="bibr">179</xref>]. Both temsirolimus and everolimus display immunosuppressive activity, derived from B and T cell proliferation inhibition from rapamycin, the molecule of which they are analogs [<xref rid="B180-cells-08-01013" ref-type="bibr">180</xref>]. As such, their toxicity profiles also include infections, hypersensitivity reactions, angioedema, nephrotoxicity with proteinuria, kidney arterial and venous thrombosis, delays in wound healing, and increased risk of second tumors and increased risk of opportunistic infections [<xref rid="B180-cells-08-01013" ref-type="bibr">180</xref>]. These rare to severe side effects are dose-limiting, but rarely lead to discontinuation of mTOR inhibitor therapies because either adjusting the dose or support medications can overcome them.</p></sec><sec id="sec17-cells-08-01013"><title>17. Synthetic Lethality</title><p>The recognition of an effective chemotherapy regimen, either monotherapy or in combination, has been achieved in clinical trials, which are largely based on clinical and empirical experience, with a focus on therapeutic efficacy and tolerable toxicity. This is an expensive and time-consuming pipeline, for which most drugs fail [<xref rid="B181-cells-08-01013" ref-type="bibr">181</xref>]. Mechanism-based drug combinations have been mostly investigated at the preclinical stages. The search for better combinations has developed many screenings, such as those that aim at synthetic lethality and drug repurposing.</p><p>Synthetic lethality screenings have been thoroughly performed for the last 10 years in the search for gene and drug synergism. These screens have identified some combinations that might result in true drug interactions, from which one single combination has reached a place in the clinic, namely, the use of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1 DNA repair associated (<italic>BRCA</italic>) gene mutated patients [<xref rid="B182-cells-08-01013" ref-type="bibr">182</xref>]. Inhibition of PARP activity induces synthetic lethality in mutated <italic>BRCA1/2</italic> cancers by selectively targeting tumor cells that fail to repair DNA double-strand breaks [<xref rid="B183-cells-08-01013" ref-type="bibr">183</xref>]. </p><p>Another promising example of the capabilities of synthetic lethality screening has been published for late ovarian cancer; the authors proposed a list of 84 new drug combinations to be tested in preclinical and clinical trials [<xref rid="B184-cells-08-01013" ref-type="bibr">184</xref>]. </p><p>We strongly believe that the expansion in knowledge of signaling pathways and networks will present innovative opportunities for improved cancer therapies.</p></sec><sec id="sec18-cells-08-01013"><title>18. Drug Repurposing</title><p>Only 5% of anticancer drugs entering phase I clinical trials are ultimately granted FDA approval [<xref rid="B185-cells-08-01013" ref-type="bibr">185</xref>]. Drug repurposing aims to identify new applications for approved or investigational drugs that differ from their original clinical indication. This strategy allows for faster development at reduced costs since preclinical and clinical data might already be available for the repurposed drug [<xref rid="B186-cells-08-01013" ref-type="bibr">186</xref>]. Several analgesics and anesthetics, and antipsychotic, antibiotic and antiprotozoal drugs, among many other classes, have already been repurposed or are being tested on an oncology setting, based on modulation of numerous cell signaling pathways commonly disrupted in cancer [<xref rid="B185-cells-08-01013" ref-type="bibr">185</xref>]. Nitazoxanide (NTZ) is an antiprotozoal drug, which has been recently shown to inhibit autophagy in glioblastoma cells [<xref rid="B187-cells-08-01013" ref-type="bibr">187</xref>]. The combination with chloroquine (CQ), a well-known antimalarial autophagy inhibitor, had a synergistic effect, with CQ sensitizing the glioma cells to NTZ. Since NTZ has been shown to cross the blood–brain barrier (BBB) in mice, this highly lipophilic compound is a potential drug for reuse to treat gliomas [<xref rid="B187-cells-08-01013" ref-type="bibr">187</xref>]. </p><p>Lipophilic antipsychotic drugs, known to cross the BBB effectively to bind to central dopamine D2 receptors and promote their therapeutic action, are able to modulate many cancer-associated intracellular signaling pathways, such as PI3K-AKT-mTOR, STAT3, and WNT [<xref rid="B188-cells-08-01013" ref-type="bibr">188</xref>], and may act as anti-cancer drugs. Chlorpromazine (CPZ), a dopamine D2 receptor antagonist, is able to cross the cell membrane and bind to FKBP-12, inhibiting the mTOR pathway, one of the most frequent points of dysregulation in cancer (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S3</xref>). This inhibition led to increased autophagic cell death in U-87 MG (glioblastoma) cells. Furthermore, CPZ inhibited tumor growth in human xenograft colon cancer and induced apoptosis in CRC cells in a p53-dependent manner mediated by c-Jun N-terminal Kinase (JNK) activation [<xref rid="B189-cells-08-01013" ref-type="bibr">189</xref>]. </p><p>Other dopamine receptor-independent pharmacological activities of antipsychotics may be used as a basis for drug repurposing. Serotonin 5-hydroxytryptamine 7 (5-HT7) receptors are expressed by astrocytes and are commonly found overexpressed in glioblastoma, and are associated with apoptosis resistance, pro-survival signaling, and malignant transformation [<xref rid="B188-cells-08-01013" ref-type="bibr">188</xref>]. Thus, the use of antipsychotic drugs that also bind and inhibit 5-HT7, the antipsychotic risperidone (RIS), could be an attractive strategy for glioblastoma treatment. Other potential anticancer properties of RIS have already been demonstrated in both in vitro and in murine models. In resistant breast and colorectal cancer models, RIS is able to inhibit ABCG2 overexpression in a dose-dependent fashion, thus being able to reduce the impact of resistance mechanisms dependent on drug efflux that may arise from long-term chemotherapy [<xref rid="B188-cells-08-01013" ref-type="bibr">188</xref>]. </p><p>Given the poor availability of efficient treatments in many cancer types (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S3</xref>), repurposing of such drugs given in combination with traditional chemotherapy and/or radiotherapy could improve cancer treatment and lead to lower doses and side effects, ultimately improving prognosis and quality of patients’ lives.</p></sec><sec id="sec19-cells-08-01013"><title>19. Conclusion and Final Considerations</title><p>Cytotoxic drugs are genotoxic, so the most common resistance mechanisms are associated with DNA homeostasis and increase detoxification as ABC transport. The resistance mechanisms of the targeted therapy are specific key changes in their targets of the signaling pathways, such as MAPK, PI3K, AKT, mTOR, and others. It is expected that the combination of chemotherapy and drugs intended to inhibit the mechanism of resistance induced by chemotherapy would increase cell death. This approach has the limitation that most inhibitors of ABC transport and MAPK receptors, PI3K, AKT, and mTOR, showed high toxicity and were not recommended for phase III clinical trial. The development of more selective inhibitors and repurposing of existing drugs are two different strategies that could be used to address this toxicity. </p><p>For the first strategy, a few examples have already been FDA approved. Initial clinical trials with pan-CDK inhibitors were very toxic and, as a consequence, did not reach phase III. Recently, three selective CDK4/6 inhibitors have been approved for metastatic breast cancer and are now being tested in various combinations for different tumors (<xref rid="cells-08-01013-t003" ref-type="table">Table 3</xref> and <xref rid="cells-08-01013-t004" ref-type="table">Table 4</xref>). Many pre-clinical and clinical studies are necessary to understand when combinations of CDK inhibitors and other therapies may be promising since both antagonist and synergic effects can be achieved [<xref rid="B190-cells-08-01013" ref-type="bibr">190</xref>]. Even for the new generation of specific CDK4/6 inhibitors, the combination with first- and second-line cytotoxic therapy in glioblastomas showed antagonist and synergic effects depending on the combination. Abemaciclib increased cell death in temozolomide-treated groups, whereas it decreased carboplatin-induced cell death in glioblastoma cell lines (Hadju et al. unpublished data). In addition to new combinations of drugs given simultaneously, alternative regimes of sequential therapies should be explored depending on the possible biological effects that can be induced. Since CDK4/6 inhibitors induce transient cell cycle arrest, they might be suitable to be used in sequential cycles. Once the cell cycle blockage is released, cytotoxic drugs might maximize DNA damage-induced cell death of synchronized S-phase cells. Therefore, profound understandings of cell biology may help in designing new strategies. </p><p>Another possibility for dealing with the high toxicity of inhibiting key components of signaling pathways of resistance mechanisms is to explore less potent inhibitors in the form of safer drugs already in use for other purposes. For this, the careful off-target studies of drugs already in use for another proposal can be tested. For example, imatinib was originally designed to inhibit BCR-ABL tyrosine kinase, and it was identified that it also inhibits platelet-derived growth factor receptor (<italic>PDGFR</italic>) and <italic>KIT</italic> proto-oncogene tyrosine kinases. Since <italic>KIT</italic> and <italic>PDGFRA</italic> mutations are observed in 85% of gastrointestinal stromal tumors (GISTs), it was also tested and approved for GIST treatment [<xref rid="B191-cells-08-01013" ref-type="bibr">191</xref>]. The list of repurposed drugs can be found on the reproDB website [<xref rid="B192-cells-08-01013" ref-type="bibr">192</xref>]. It is urgent, however, that drug combinations are tested based on the mechanism of action, off-target, and resistance mechanisms, including drugs already designed for another purpose. This review collected the known off-target and resistance mechanism data of cytotoxic drugs (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S1</xref>) and anticancer-targeted therapies (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S2</xref>) that were FDA-approved up to May 2019, organized by drug classification. This effort hopefully will help build future experiments exploring new combinations of drugs, including known off-targets that interfere directly with resistance mechanisms of other drugs.</p><p>The effort of looking for new combinations that target the resistance mechanisms should not be limited to anticancer drugs but should also include repurposing drugs for other diseases. For example, lipophilic antipsychotic drugs and others that can inhibit the major mechanism of resistance of the target therapy, such as PI3K-AKT-mTOR and STAT3, [<xref rid="B188-cells-08-01013" ref-type="bibr">188</xref>] can be tested with a wide range of target therapies and cancers (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S2</xref>). Studies are particularly needed for tumors whose patients present a 5-year mean survival that is below 20% and have limited or even no FDA-approved combinations (<xref ref-type="app" rid="app1-cells-08-01013">Supplementary Table S3</xref>).</p><p>It is worth noting that the literature search for the resistance mechanisms discussed in this review was limited to the direct effectors of signaling pathways. However, let us not forget that resistance mechanisms might also be triggered by indirect modulation of signaling pathways, such as transcription factors and regulatory elements (enhancers and silencers, regulatory RNAs—lncRNA, miRNA). Moreover, most indirect pathways represent network-signaling interactions in which they might be tumor- or cell-type specific, with putative different triggers and modulations by specific co-repressors and/or co-activators. These also represent relevant targets for drug development, but more research will be needed, including high-throughput screening. </p><p>Bioinformatics and many preclinical studies are needed to understand the mechanisms of drug interactions for combination therapy. Since most signaling pathways are overlapping, with several points of interaction with other pathways, and show compensatory mechanisms, it is certainly a difficult task to predict this complex network, especially when particular mutations of tumor cells are also taken into account. One may wonder whether it is not more efficient to screen patients to the best protocols available instead of using a "fit the patient to the drug” approach, an unintended design of clinical trials for drug development. Would not it be beneficial, ethical, and possibly more economical for patients and drug development to avoid unnecessary exposure to inefficient protocols? We understand that both traditional trials and personalized therapy might (or should) be supported by individual, fast, and efficient targeting and/or drug screening, before any first-line treatments to identify intrinsic resistances and sensitivities. This might be achieved by designing faster high-throughput screenings with patient-derived tissue samples, such as first-generation organoid cultures [<xref rid="B193-cells-08-01013" ref-type="bibr">193</xref>]. Affordable protocols for organoid cultures of the major tissues affected by human cancers are urgently needed.</p></sec></body><back><app-group><app id="app1-cells-08-01013"><title>Supplementary Materials</title><supplementary-material content-type="local-data" id="cells-08-01013-s001"><media xlink:href="cells-08-01013-s001.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><p>The following are available online at <uri xlink:href="https://www.mdpi.com/2073-4409/8/9/1013/s1">https://www.mdpi.com/2073-4409/8/9/1013/s1</uri>, Supplementary Table S1. Summary of FDA-approved anticancer cytotoxic drugs at May 2019. Supplementary Table S2. Summary of FDA-approved anticancer targeted therapies at May 2019. Supplementary Table S3. Approved drug combination options are limited, even when recommended in first-line therapy for the most prevalent and fatal cancer types. </p></app></app-group><notes><title>Author Contributions</title><p>Conceptualization, J.M.A.D and H.L.B.; Validation, J.M.A.D., A.S.O.S. and L.C.M.S.; Writing—Original Draft Preparation, J.M.A.D., A.S.O.S., L.C.M.S. and H.L.B.; Writing—Review & Editing, J.M.A.D., L.C.M.S. and H.L.B.; Funding Acquisition, H.L.B.</p></notes><notes><title>Funding</title><p>This research was funded by the Brazilian funding agencies: National Council for Scientific and Technological Development (CNPq), Coordination for the Improvement of Higher Education Personnel (CAPES), and Foundation Carlos Chagas Filho Research Support of the State of Rio de Janeiro (FAPERJ).</p></notes><notes notes-type="COI-statement"><title>Conflicts of Interest</title><p>The authors declare no conflict of interest.</p></notes><ref-list><title>References</title><ref id="B1-cells-08-01013"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gilman</surname><given-names>A.</given-names></name></person-group><article-title>The initial clinical trial of nitrogen mustard</article-title><source>Am. J. Surg.</source><year>1963</year><volume>105</volume><fpage>574</fpage><lpage>578</lpage><pub-id pub-id-type="doi">10.1016/0002-9610(63)90232-0</pub-id><pub-id pub-id-type="pmid">13947966</pub-id></element-citation></ref><ref id="B2-cells-08-01013"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>DeVita</surname><given-names>V.T.</given-names></name><name><surname>Chu</surname><given-names>E.</given-names></name></person-group><article-title>A History of Cancer Chemotherapy</article-title><source>Cancer Res.</source><year>2008</year><volume>68</volume><fpage>8643</fpage><lpage>8653</lpage><pub-id pub-id-type="doi">10.1158/0008-5472.CAN-07-6611</pub-id><pub-id pub-id-type="pmid">18974103</pub-id></element-citation></ref><ref id="B3-cells-08-01013"><label>3.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mokhtari</surname><given-names>R.B.</given-names></name><name><surname>Homayouni</surname><given-names>T.S.</given-names></name><name><surname>Baluch</surname><given-names>N.</given-names></name><name><surname>Morgatskaya</surname><given-names>E.</given-names></name><name><surname>Kumar</surname><given-names>S.</given-names></name><name><surname>Das</surname><given-names>B.</given-names></name><name><surname>Yeger</surname><given-names>H.</given-names></name></person-group><article-title>Combination therapy in combating cancer</article-title><source>Oncotarget</source><year>2015</year><volume>8</volume><fpage>38022</fpage><lpage>38043</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.16723</pub-id><pub-id pub-id-type="pmid">28410237</pub-id></element-citation></ref><ref id="B4-cells-08-01013"><label>4.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mansoori</surname><given-names>B.</given-names></name><name><surname>Mohammadi</surname><given-names>A.</given-names></name><name><surname>Davudian</surname><given-names>S.</given-names></name><name><surname>Shirjang</surname><given-names>S.</given-names></name><name><surname>Baradaran</surname><given-names>B.</given-names></name></person-group><article-title>The Different Mechanisms of Cancer Drug Resistance: A Brief Review</article-title><source>Adv. Pharm. Bull.</source><year>2017</year><volume>7</volume><fpage>339</fpage><lpage>348</lpage><pub-id pub-id-type="doi">10.15171/apb.2017.041</pub-id><pub-id pub-id-type="pmid">29071215</pub-id></element-citation></ref><ref id="B5-cells-08-01013"><label>5.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goodman</surname><given-names>A.M.</given-names></name><name><surname>Kato</surname><given-names>S.</given-names></name><name><surname>Bazhenova</surname><given-names>L.</given-names></name><name><surname>Patel</surname><given-names>S.P.</given-names></name><name><surname>Frampton</surname><given-names>G.M.</given-names></name><name><surname>Miller</surname><given-names>V.</given-names></name><name><surname>Stephens</surname><given-names>P.J.</given-names></name><name><surname>Daniels</surname><given-names>G.A.</given-names></name><name><surname>Kurzrock</surname><given-names>R.</given-names></name></person-group><article-title>Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers</article-title><source>Mol. Cancer Ther.</source><year>2017</year><volume>16</volume><fpage>2598</fpage><lpage>2608</lpage><pub-id pub-id-type="doi">10.1158/1535-7163.MCT-17-0386</pub-id><pub-id pub-id-type="pmid">28835386</pub-id></element-citation></ref><ref id="B6-cells-08-01013"><label>6.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jia</surname><given-names>Q.</given-names></name><name><surname>Wu</surname><given-names>W.</given-names></name><name><surname>Wang</surname><given-names>Y.</given-names></name><name><surname>Alexander</surname><given-names>P.B.</given-names></name><name><surname>Sun</surname><given-names>C.</given-names></name><name><surname>Gong</surname><given-names>Z.</given-names></name><name><surname>Cheng</surname><given-names>J.-N.</given-names></name><name><surname>Sun</surname><given-names>H.</given-names></name><name><surname>Guan</surname><given-names>Y.</given-names></name><name><surname>Xia</surname><given-names>X.</given-names></name><etal></etal></person-group><article-title>Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer</article-title><source>Nat. Commun.</source><year>2018</year><volume>9</volume><fpage>5361</fpage><pub-id pub-id-type="doi">10.1038/s41467-018-07767-w</pub-id><pub-id pub-id-type="pmid">30560866</pub-id></element-citation></ref><ref id="B7-cells-08-01013"><label>7.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bruce</surname><given-names>W.R.</given-names></name><name><surname>Meeker</surname><given-names>B.E.</given-names></name></person-group><article-title>Comparison of the sensitivity of hematopoietic colony-forming cells in different proliferative states to 5-fluorouracil</article-title><source>J. Natl. Cancer Inst.</source><year>1967</year><volume>38</volume><fpage>401</fpage><lpage>405</lpage><pub-id pub-id-type="pmid">6022612</pub-id></element-citation></ref><ref id="B8-cells-08-01013"><label>8.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hill</surname><given-names>B.T.</given-names></name><name><surname>Baserga</surname><given-names>R.</given-names></name></person-group><article-title>The cell cycle and its significance for cancer treatment</article-title><source>Cancer Treat. Rev.</source><year>1975</year><volume>2</volume><fpage>159</fpage><lpage>175</lpage><pub-id pub-id-type="doi">10.1016/S0305-7372(75)80001-6</pub-id><pub-id pub-id-type="pmid">1104161</pub-id></element-citation></ref><ref id="B9-cells-08-01013"><label>9.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Espinosa</surname><given-names>E.</given-names></name><name><surname>Zamora</surname><given-names>P.</given-names></name><name><surname>Feliu</surname><given-names>J.</given-names></name><name><surname>González Barón</surname><given-names>M.</given-names></name></person-group><article-title>Classification of anticancer drugs—A new system based on therapeutic targets</article-title><source>Cancer Treat. Rev.</source><year>2003</year><volume>29</volume><fpage>515</fpage><lpage>523</lpage><pub-id pub-id-type="doi">10.1016/S0305-7372(03)00116-6</pub-id><pub-id pub-id-type="pmid">14585261</pub-id></element-citation></ref><ref id="B10-cells-08-01013"><label>10.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>X.-Z.</given-names></name></person-group><article-title>A new classification system of anticancer drugs—Based on cell biological mechanisms</article-title><source>Med. Hypotheses</source><year>2006</year><volume>66</volume><fpage>883</fpage><lpage>887</lpage><pub-id pub-id-type="doi">10.1016/j.mehy.2005.11.036</pub-id><pub-id pub-id-type="pmid">16414204</pub-id></element-citation></ref><ref id="B11-cells-08-01013"><label>11.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dutt</surname><given-names>R.</given-names></name><name><surname>Madan</surname><given-names>A.K.</given-names></name></person-group><article-title>Classification Models for Anticancer Activity</article-title><source>Curr. Top. Med. Chem.</source><year>2013</year><volume>12</volume><fpage>2705</fpage><lpage>2726</lpage><pub-id pub-id-type="doi">10.2174/1568026611212240002</pub-id></element-citation></ref><ref id="B12-cells-08-01013"><label>12.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pritchard</surname><given-names>J.R.</given-names></name><name><surname>Bruno</surname><given-names>P.M.</given-names></name><name><surname>Gilbert</surname><given-names>L.A.</given-names></name><name><surname>Capron</surname><given-names>K.L.</given-names></name><name><surname>Lauffenburger</surname><given-names>D.A.</given-names></name><name><surname>Hemann</surname><given-names>M.T.</given-names></name></person-group><article-title>Defining principles of combination drug mechanisms of action</article-title><source>Proc. Natl. Acad. Sci.</source><year>2013</year><volume>110</volume><fpage>E170</fpage><lpage>E179</lpage><pub-id pub-id-type="doi">10.1073/pnas.1210419110</pub-id><pub-id pub-id-type="pmid">23251029</pub-id></element-citation></ref><ref id="B13-cells-08-01013"><label>13.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wishart</surname><given-names>D.S.</given-names></name><name><surname>Feunang</surname><given-names>Y.D.</given-names></name><name><surname>Guo</surname><given-names>A.C.</given-names></name><name><surname>Lo</surname><given-names>E.J.</given-names></name><name><surname>Marcu</surname><given-names>A.</given-names></name><name><surname>Grant</surname><given-names>J.R.</given-names></name><name><surname>Sajed</surname><given-names>T.</given-names></name><name><surname>Johnson</surname><given-names>D.</given-names></name><name><surname>Li</surname><given-names>C.</given-names></name><name><surname>Sayeeda</surname><given-names>Z.</given-names></name><etal></etal></person-group><article-title>DrugBank 5.0: a major update to the DrugBank database for 2018</article-title><source>Nucleic Acids Res.</source><year>2018</year><volume>46</volume><fpage>D1074</fpage><lpage>D1082</lpage><pub-id pub-id-type="doi">10.1093/nar/gkx1037</pub-id><pub-id pub-id-type="pmid">29126136</pub-id></element-citation></ref><ref id="B14-cells-08-01013"><label>14.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Preissner</surname><given-names>S.</given-names></name><name><surname>Kroll</surname><given-names>K.</given-names></name><name><surname>Dunkel</surname><given-names>M.</given-names></name><name><surname>Senger</surname><given-names>C.</given-names></name><name><surname>Goldsobel</surname><given-names>G.</given-names></name><name><surname>Kuzman</surname><given-names>D.</given-names></name><name><surname>Guenther</surname><given-names>S.</given-names></name><name><surname>Winnenburg</surname><given-names>R.</given-names></name><name><surname>Schroeder</surname><given-names>M.</given-names></name><name><surname>Preissner</surname><given-names>R.</given-names></name></person-group><article-title>SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions</article-title><source>Nucleic Acids Res.</source><year>2010</year><volume>38</volume><fpage>D237</fpage><lpage>D243</lpage><pub-id pub-id-type="doi">10.1093/nar/gkp970</pub-id><pub-id pub-id-type="pmid">19934256</pub-id></element-citation></ref><ref id="B15-cells-08-01013"><label>15.</label><element-citation publication-type="journal"><article-title>Mechanism matters</article-title><source>Nat. Med.</source><year>2010</year><volume>16</volume><fpage>347</fpage><pub-id pub-id-type="doi">10.1038/nm0410-347</pub-id><pub-id pub-id-type="pmid">20376007</pub-id></element-citation></ref><ref id="B16-cells-08-01013"><label>16.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Juliano</surname><given-names>R.L.L.</given-names></name><name><surname>Ling</surname><given-names>V.</given-names></name></person-group><article-title>A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants</article-title><source>Biochim. Biophys. Acta - Biomembr.</source><year>1976</year><volume>455</volume><fpage>152</fpage><lpage>162</lpage><pub-id pub-id-type="doi">10.1016/0005-2736(76)90160-7</pub-id></element-citation></ref><ref id="B17-cells-08-01013"><label>17.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Robey</surname><given-names>R.W.</given-names></name><name><surname>Pluchino</surname><given-names>K.M.</given-names></name><name><surname>Hall</surname><given-names>M.D.</given-names></name><name><surname>Fojo</surname><given-names>A.T.</given-names></name><name><surname>Bates</surname><given-names>S.E.</given-names></name><name><surname>Gottesman</surname><given-names>M.M.</given-names></name></person-group><article-title>Revisiting the role of ABC transporters in multidrug-resistant cancer</article-title><source>Nat. Rev. Cancer</source><year>2018</year><volume>18</volume><fpage>452</fpage><lpage>464</lpage><pub-id pub-id-type="doi">10.1038/s41568-018-0005-8</pub-id><pub-id pub-id-type="pmid">29643473</pub-id></element-citation></ref><ref id="B18-cells-08-01013"><label>18.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gottesman</surname><given-names>M.M.</given-names></name><name><surname>Fojo</surname><given-names>T.</given-names></name><name><surname>Bates</surname><given-names>S.E.</given-names></name></person-group><article-title>Multidrug resistance in cancer: role of ATP–dependent transporters</article-title><source>Nat. Rev. Cancer</source><year>2002</year><volume>2</volume><fpage>48</fpage><lpage>58</lpage><pub-id pub-id-type="doi">10.1038/nrc706</pub-id><pub-id pub-id-type="pmid">11902585</pub-id></element-citation></ref><ref id="B19-cells-08-01013"><label>19.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Szakács</surname><given-names>G.</given-names></name><name><surname>Paterson</surname><given-names>J.K.</given-names></name><name><surname>Ludwig</surname><given-names>J.A.</given-names></name><name><surname>Booth-Genthe</surname><given-names>C.</given-names></name><name><surname>Gottesman</surname><given-names>M.M.</given-names></name></person-group><article-title>Targeting multidrug resistance in cancer</article-title><source>Nat. Rev. Drug Discov.</source><year>2006</year><volume>5</volume><fpage>219</fpage><lpage>234</lpage><pub-id pub-id-type="doi">10.1038/nrd1984</pub-id><pub-id pub-id-type="pmid">16518375</pub-id></element-citation></ref><ref id="B20-cells-08-01013"><label>20.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Patel</surname><given-names>C.</given-names></name><name><surname>Stenke</surname><given-names>L.</given-names></name><name><surname>Varma</surname><given-names>S.</given-names></name><name><surname>Lindberg</surname><given-names>M.L.</given-names></name><name><surname>Björkholm</surname><given-names>M.</given-names></name><name><surname>Sjöberg</surname><given-names>J.</given-names></name><name><surname>Viktorsson</surname><given-names>K.</given-names></name><name><surname>Lewensohn</surname><given-names>R.</given-names></name><name><surname>Landgren</surname><given-names>O.</given-names></name><name><surname>Gottesman</surname><given-names>M.M.</given-names></name><etal></etal></person-group><article-title>Multidrug resistance in relapsed acute myeloid leukemia: Evidence of biological heterogeneity</article-title><source>Cancer</source><year>2013</year><volume>119</volume><fpage>3076</fpage><lpage>3083</lpage><pub-id pub-id-type="doi">10.1002/cncr.28098</pub-id><pub-id pub-id-type="pmid">23674237</pub-id></element-citation></ref><ref id="B21-cells-08-01013"><label>21.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bartholomae</surname><given-names>S.</given-names></name><name><surname>Gruhn</surname><given-names>B.</given-names></name><name><surname>Debatin</surname><given-names>K.-M.</given-names></name><name><surname>Zimmermann</surname><given-names>M.</given-names></name><name><surname>Creutzig</surname><given-names>U.</given-names></name><name><surname>Reinhardt</surname><given-names>D.</given-names></name><name><surname>Steinbach</surname><given-names>D.</given-names></name></person-group><article-title>Coexpression of Multiple ABC-Transporters is Strongly Associated with Treatment Response in Childhood Acute Myeloid Leukemia</article-title><source>Pediatr. Blood Cancer</source><year>2016</year><volume>63</volume><fpage>242</fpage><lpage>247</lpage><pub-id pub-id-type="doi">10.1002/pbc.25785</pub-id><pub-id pub-id-type="pmid">26512967</pub-id></element-citation></ref><ref id="B22-cells-08-01013"><label>22.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Marzac</surname><given-names>C.</given-names></name><name><surname>Garrido</surname><given-names>E.</given-names></name><name><surname>Tang</surname><given-names>R.</given-names></name><name><surname>Fava</surname><given-names>F.</given-names></name><name><surname>Hirsch</surname><given-names>P.</given-names></name><name><surname>De Benedictis</surname><given-names>C.</given-names></name><name><surname>Corre</surname><given-names>E.</given-names></name><name><surname>Lapusan</surname><given-names>S.</given-names></name><name><surname>Lallemand</surname><given-names>J.-Y.</given-names></name><name><surname>Marie</surname><given-names>J.-P.</given-names></name><etal></etal></person-group><article-title>ATP Binding Cassette transporters associated with chemoresistance: transcriptional profiling in extreme cohorts and their prognostic impact in a cohort of 281 acute myeloid leukemia patients</article-title><source>Haematologica</source><year>2011</year><volume>96</volume><fpage>1293</fpage><lpage>1301</lpage><pub-id pub-id-type="doi">10.3324/haematol.2010.031823</pub-id><pub-id pub-id-type="pmid">21606172</pub-id></element-citation></ref><ref id="B23-cells-08-01013"><label>23.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cui</surname><given-names>H.</given-names></name><name><surname>Zhang</surname><given-names>A.</given-names></name><name><surname>Chen</surname><given-names>M.</given-names></name><name><surname>Liu</surname><given-names>J.</given-names></name></person-group><article-title>ABC Transporter Inhibitors in Reversing Multidrug Resistance to Chemotherapy</article-title><source>Curr. Drug Targets</source><year>2015</year><volume>16</volume><fpage>1356</fpage><lpage>1371</lpage><pub-id pub-id-type="doi">10.2174/1389450116666150330113506</pub-id><pub-id pub-id-type="pmid">25901528</pub-id></element-citation></ref><ref id="B24-cells-08-01013"><label>24.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Karthikeyan</surname><given-names>S.</given-names></name><name><surname>Hoti</surname><given-names>S.L.</given-names></name></person-group><article-title>Development of Fourth Generation ABC Inhibitors from Natural Products: A Novel Approach to Overcome Cancer Multidrug Resistance</article-title><source>Anticancer. Agents Med. Chem.</source><year>2015</year><volume>15</volume><fpage>605</fpage><lpage>615</lpage><pub-id pub-id-type="doi">10.2174/1871520615666150113103439</pub-id><pub-id pub-id-type="pmid">25584696</pub-id></element-citation></ref><ref id="B25-cells-08-01013"><label>25.</label><element-citation publication-type="gov"><article-title>National Cancer Institute Bleomycin Sulfate</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://www.cancer.gov/about-cancer/treatment/drugs/bleomycin">https://www.cancer.gov/about-cancer/treatment/drugs/bleomycin</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B26-cells-08-01013"><label>26.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zheng</surname><given-names>W.</given-names></name><name><surname>Johnston</surname><given-names>S.A.</given-names></name></person-group><article-title>The Nucleic Acid Binding Activity of Bleomycin Hydrolase Is Involved in Bleomycin Detoxification</article-title><source>Mol. Cell. Biol.</source><year>1998</year><volume>18</volume><fpage>3580</fpage><lpage>3585</lpage><pub-id pub-id-type="doi">10.1128/MCB.18.6.3580</pub-id><pub-id pub-id-type="pmid">9584198</pub-id></element-citation></ref><ref id="B27-cells-08-01013"><label>27.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lazo</surname><given-names>J.S.</given-names></name><name><surname>Boland</surname><given-names>C.J.</given-names></name><name><surname>Schwartz</surname><given-names>P.E.</given-names></name></person-group><article-title>Bleomycin hydrolase activity and cytotoxicity in human tumors</article-title><source>Cancer Res.</source><year>1982</year><volume>42</volume><fpage>4026</fpage><lpage>4031</lpage><pub-id pub-id-type="pmid">6179595</pub-id></element-citation></ref><ref id="B28-cells-08-01013"><label>28.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lefterov</surname><given-names>I.M.</given-names></name><name><surname>Koldamova</surname><given-names>R.P.</given-names></name><name><surname>King</surname><given-names>J.</given-names></name><name><surname>Lazo</surname><given-names>J.S.</given-names></name></person-group><article-title>The C-terminus of human bleomycin hydrolase is required for protection against bleomycin-induced chromosomal damage</article-title><source>Mutat. Res. Mol. Mech. Mutagen.</source><year>1998</year><volume>421</volume><fpage>1</fpage><lpage>7</lpage><pub-id pub-id-type="doi">10.1016/S0027-5107(98)00148-1</pub-id></element-citation></ref><ref id="B29-cells-08-01013"><label>29.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dortet</surname><given-names>L.</given-names></name><name><surname>Girlich</surname><given-names>D.</given-names></name><name><surname>Virlouvet</surname><given-names>A.-L.</given-names></name><name><surname>Poirel</surname><given-names>L.</given-names></name><name><surname>Nordmann</surname><given-names>P.</given-names></name><name><surname>Iorga</surname><given-names>B.I.</given-names></name><name><surname>Naas</surname><given-names>T.</given-names></name></person-group><article-title>Characterization of BRP MBL, the Bleomycin Resistance Protein Associated with the Carbapenemase NDM</article-title><source>Antimicrob. Agents Chemother.</source><year>2017</year><volume>61</volume><fpage>e02413</fpage><lpage>e02416</lpage><pub-id pub-id-type="doi">10.1128/AAC.02413-16</pub-id><pub-id pub-id-type="pmid">28069656</pub-id></element-citation></ref><ref id="B30-cells-08-01013"><label>30.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ishikawa</surname><given-names>T.</given-names></name></person-group><article-title>ATP/Mg2+-dependent cardiac transport system for glutathione S-conjugates. A study using rat heart sarcolemma vesicles</article-title><source>J. Biol. Chem.</source><year>1989</year><volume>264</volume><fpage>17343</fpage><lpage>17348</lpage><pub-id pub-id-type="pmid">2793858</pub-id></element-citation></ref><ref id="B31-cells-08-01013"><label>31.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Muller</surname><given-names>M.</given-names></name><name><surname>Meijer</surname><given-names>C.</given-names></name><name><surname>Zaman</surname><given-names>G.J.</given-names></name><name><surname>Borst</surname><given-names>P.</given-names></name><name><surname>Scheper</surname><given-names>R.J.</given-names></name><name><surname>Mulder</surname><given-names>N.H.</given-names></name><name><surname>de Vries</surname><given-names>E.G.</given-names></name><name><surname>Jansen</surname><given-names>P.L.</given-names></name></person-group><article-title>Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport</article-title><source>Proc. Natl. Acad. Sci.</source><year>1994</year><volume>91</volume><fpage>13033</fpage><lpage>13037</lpage><pub-id pub-id-type="doi">10.1073/pnas.91.26.13033</pub-id><pub-id pub-id-type="pmid">7809167</pub-id></element-citation></ref><ref id="B32-cells-08-01013"><label>32.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brechbuhl</surname><given-names>H.M.</given-names></name><name><surname>Gould</surname><given-names>N.</given-names></name><name><surname>Kachadourian</surname><given-names>R.</given-names></name><name><surname>Riekhof</surname><given-names>W.R.</given-names></name><name><surname>Voelker</surname><given-names>D.R.</given-names></name><name><surname>Day</surname><given-names>B.J.</given-names></name></person-group><article-title>Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2</article-title><source>J. Biol. Chem.</source><year>2010</year><volume>285</volume><fpage>16582</fpage><lpage>16587</lpage><pub-id pub-id-type="doi">10.1074/jbc.M109.090506</pub-id><pub-id pub-id-type="pmid">20332504</pub-id></element-citation></ref><ref id="B33-cells-08-01013"><label>33.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>Y.-L.</given-names></name><name><surname>Li</surname><given-names>B.-Y.</given-names></name><name><surname>Yang</surname><given-names>R.</given-names></name><name><surname>Xia</surname><given-names>L.-Y.</given-names></name><name><surname>Fan</surname><given-names>A.-L.</given-names></name><name><surname>Chu</surname><given-names>Y.-C.</given-names></name><name><surname>Wang</surname><given-names>L.-J.</given-names></name><name><surname>Wang</surname><given-names>Z.-C.</given-names></name><name><surname>Jiang</surname><given-names>A.-Q.</given-names></name><name><surname>Zhu</surname><given-names>H.-L.</given-names></name></person-group><article-title>A class of novel tubulin polymerization inhibitors exert effective anti-tumor activity via mitotic catastrophe</article-title><source>Eur. J. Med. Chem.</source><year>2019</year><volume>163</volume><fpage>896</fpage><lpage>910</lpage><pub-id pub-id-type="doi">10.1016/j.ejmech.2018.12.030</pub-id><pub-id pub-id-type="pmid">30580241</pub-id></element-citation></ref><ref id="B34-cells-08-01013"><label>34.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dumontet</surname><given-names>C.</given-names></name><name><surname>Jordan</surname><given-names>M.A.</given-names></name></person-group><article-title>Microtubule-binding agents: a dynamic field of cancer therapeutics</article-title><source>Nat. Rev. Drug Discov.</source><year>2010</year><volume>9</volume><fpage>790</fpage><lpage>803</lpage><pub-id pub-id-type="doi">10.1038/nrd3253</pub-id><pub-id pub-id-type="pmid">20885410</pub-id></element-citation></ref><ref id="B35-cells-08-01013"><label>35.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cheung</surname><given-names>C.H.A.</given-names></name><name><surname>Wu</surname><given-names>S.-Y.</given-names></name><name><surname>Lee</surname><given-names>T.-R.</given-names></name><name><surname>Chang</surname><given-names>C.-Y.</given-names></name><name><surname>Wu</surname><given-names>J.-S.</given-names></name><name><surname>Hsieh</surname><given-names>H.-P.</given-names></name><name><surname>Chang</surname><given-names>J.-Y.</given-names></name></person-group><article-title>Cancer Cells Acquire Mitotic Drug Resistance Properties Through Beta I-Tubulin Mutations and Alterations in the Expression of Beta-Tubulin Isotypes</article-title><source>PLoS ONE</source><year>2010</year><volume>5</volume><elocation-id>e12564</elocation-id><pub-id pub-id-type="doi">10.1371/journal.pone.0012564</pub-id><pub-id pub-id-type="pmid">20838440</pub-id></element-citation></ref><ref id="B36-cells-08-01013"><label>36.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hari</surname><given-names>M.</given-names></name><name><surname>Wang</surname><given-names>Y.</given-names></name><name><surname>Veeraraghavan</surname><given-names>S.</given-names></name><name><surname>Cabral</surname><given-names>F.</given-names></name></person-group><article-title>Mutations in alpha- and beta-tubulin that stabilize microtubules and confer resistance to colcemid and vinblastine</article-title><source>Mol. Cancer Ther.</source><year>2003</year><volume>2</volume><fpage>597</fpage><lpage>605</lpage><pub-id pub-id-type="pmid">12883031</pub-id></element-citation></ref><ref id="B37-cells-08-01013"><label>37.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yin</surname><given-names>S.</given-names></name><name><surname>Bhattacharya</surname><given-names>R.</given-names></name><name><surname>Cabral</surname><given-names>F.</given-names></name></person-group><article-title>Human Mutations That Confer Paclitaxel Resistance</article-title><source>Mol. Cancer Ther.</source><year>2010</year><volume>9</volume><fpage>327</fpage><lpage>335</lpage><pub-id pub-id-type="doi">10.1158/1535-7163.MCT-09-0674</pub-id><pub-id pub-id-type="pmid">20103599</pub-id></element-citation></ref><ref id="B38-cells-08-01013"><label>38.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Orr</surname><given-names>G.A.</given-names></name><name><surname>Verdier-Pinard</surname><given-names>P.</given-names></name><name><surname>McDaid</surname><given-names>H.</given-names></name><name><surname>Horwitz</surname><given-names>S.B.</given-names></name></person-group><article-title>Mechanisms of Taxol resistance related to microtubules</article-title><source>Oncogene</source><year>2003</year><volume>22</volume><fpage>7280</fpage><lpage>7295</lpage><pub-id pub-id-type="doi">10.1038/sj.onc.1206934</pub-id><pub-id pub-id-type="pmid">14576838</pub-id></element-citation></ref><ref id="B39-cells-08-01013"><label>39.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Binaschi</surname><given-names>M.</given-names></name><name><surname>Zunino</surname><given-names>F.</given-names></name><name><surname>Capranico</surname><given-names>G.</given-names></name></person-group><article-title>Mechanism of action of DNA topoisomerase inhibitors</article-title><source>Stem Cells</source><year>1995</year><volume>13</volume><fpage>369</fpage><lpage>379</lpage><pub-id pub-id-type="doi">10.1002/stem.5530130408</pub-id><pub-id pub-id-type="pmid">7549896</pub-id></element-citation></ref><ref id="B40-cells-08-01013"><label>40.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hevener</surname><given-names>K.</given-names></name><name><surname>Verstak</surname><given-names>T.A.</given-names></name><name><surname>Lutat</surname><given-names>K.E.</given-names></name><name><surname>Riggsbee</surname><given-names>D.L.</given-names></name><name><surname>Mooney</surname><given-names>J.W.</given-names></name></person-group><article-title>Recent developments in topoisomerase-targeted cancer chemotherapy</article-title><source>Acta Pharm. Sin. B</source><year>2018</year><volume>8</volume><fpage>844</fpage><lpage>861</lpage><pub-id pub-id-type="doi">10.1016/j.apsb.2018.07.008</pub-id><pub-id pub-id-type="pmid">30505655</pub-id></element-citation></ref><ref id="B41-cells-08-01013"><label>41.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sabini</surname><given-names>E.</given-names></name><name><surname>Hazra</surname><given-names>S.</given-names></name><name><surname>Konrad</surname><given-names>M.</given-names></name><name><surname>Lavie</surname><given-names>A.</given-names></name></person-group><article-title>Elucidation of Different Binding Modes of Purine Nucleosides to Human Deoxycytidine Kinase</article-title><source>J. Med. Chem.</source><year>2008</year><volume>51</volume><fpage>4219</fpage><lpage>4225</lpage><pub-id pub-id-type="doi">10.1021/jm800134t</pub-id><pub-id pub-id-type="pmid">18570408</pub-id></element-citation></ref><ref id="B42-cells-08-01013"><label>42.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nathanson</surname><given-names>D.A.</given-names></name><name><surname>Armijo</surname><given-names>A.L.</given-names></name><name><surname>Tom</surname><given-names>M.</given-names></name><name><surname>Li</surname><given-names>Z.</given-names></name><name><surname>Dimitrova</surname><given-names>E.</given-names></name><name><surname>Austin</surname><given-names>W.R.</given-names></name><name><surname>Nomme</surname><given-names>J.</given-names></name><name><surname>Campbell</surname><given-names>D.O.</given-names></name><name><surname>Ta</surname><given-names>L.</given-names></name><name><surname>Le</surname><given-names>T.M.</given-names></name><etal></etal></person-group><article-title>Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication</article-title><source>J. Exp. Med.</source><year>2014</year><volume>211</volume><fpage>473</fpage><lpage>486</lpage><pub-id pub-id-type="doi">10.1084/jem.20131738</pub-id><pub-id pub-id-type="pmid">24567448</pub-id></element-citation></ref><ref id="B43-cells-08-01013"><label>43.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sarkaria</surname><given-names>J.N.</given-names></name><name><surname>Kitange</surname><given-names>G.J.</given-names></name><name><surname>James</surname><given-names>C.D.</given-names></name><name><surname>Plummer</surname><given-names>R.</given-names></name><name><surname>Calvert</surname><given-names>H.</given-names></name><name><surname>Weller</surname><given-names>M.</given-names></name><name><surname>Wick</surname><given-names>W.</given-names></name></person-group><article-title>Mechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma</article-title><source>Clin. Cancer Res.</source><year>2008</year><volume>14</volume><fpage>2900</fpage><lpage>2908</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.CCR-07-1719</pub-id><pub-id pub-id-type="pmid">18483356</pub-id></element-citation></ref><ref id="B44-cells-08-01013"><label>44.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hegi</surname><given-names>M.E.</given-names></name><name><surname>Diserens</surname><given-names>A.-C.</given-names></name><name><surname>Gorlia</surname><given-names>T.</given-names></name><name><surname>Hamou</surname><given-names>M.-F.</given-names></name><name><surname>de Tribolet</surname><given-names>N.</given-names></name><name><surname>Weller</surname><given-names>M.</given-names></name><name><surname>Kros</surname><given-names>J.M.</given-names></name><name><surname>Hainfellner</surname><given-names>J.A.</given-names></name><name><surname>Mason</surname><given-names>W.</given-names></name><name><surname>Mariani</surname><given-names>L.</given-names></name><etal></etal></person-group><article-title>MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma</article-title><source>N. Engl. J. Med.</source><year>2005</year><volume>352</volume><fpage>997</fpage><lpage>1003</lpage><pub-id pub-id-type="doi">10.1056/NEJMoa043331</pub-id><pub-id pub-id-type="pmid">15758010</pub-id></element-citation></ref><ref id="B45-cells-08-01013"><label>45.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hientz</surname><given-names>K.</given-names></name><name><surname>Mohr</surname><given-names>A.</given-names></name><name><surname>Bhakta-Guha</surname><given-names>D.</given-names></name><name><surname>Efferth</surname><given-names>T.</given-names></name></person-group><article-title>The role of p53 in cancer drug resistance and targeted chemotherapy</article-title><source>Oncotarget</source><year>2017</year><volume>8</volume><fpage>8921</fpage><lpage>8946</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.13475</pub-id><pub-id pub-id-type="pmid">27888811</pub-id></element-citation></ref><ref id="B46-cells-08-01013"><label>46.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Xia</surname><given-names>L.</given-names></name><name><surname>Tan</surname><given-names>S.</given-names></name><name><surname>Zhou</surname><given-names>Y.</given-names></name><name><surname>Lin</surname><given-names>J.</given-names></name><name><surname>Wang</surname><given-names>H.</given-names></name><name><surname>Oyang</surname><given-names>L.</given-names></name><name><surname>Tian</surname><given-names>Y.</given-names></name><name><surname>Liu</surname><given-names>L.</given-names></name><name><surname>Su</surname><given-names>M.</given-names></name><name><surname>Wang</surname><given-names>H.</given-names></name><etal></etal></person-group><article-title>Role of the NF-kappa;B-signaling pathway in cancer</article-title><source>Onco. Targets. Ther.</source><year>2018</year><volume>11</volume><fpage>2063</fpage><lpage>2073</lpage><pub-id pub-id-type="doi">10.2147/OTT.S161109</pub-id><pub-id pub-id-type="pmid">29695914</pub-id></element-citation></ref><ref id="B47-cells-08-01013"><label>47.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tanei</surname><given-names>T.</given-names></name><name><surname>Morimoto</surname><given-names>K.</given-names></name><name><surname>Shimazu</surname><given-names>K.</given-names></name><name><surname>Kim</surname><given-names>S.J.</given-names></name><name><surname>Tanji</surname><given-names>Y.</given-names></name><name><surname>Taguchi</surname><given-names>T.</given-names></name><name><surname>Tamaki</surname><given-names>Y.</given-names></name><name><surname>Noguchi</surname><given-names>S.</given-names></name></person-group><article-title>Association of Breast Cancer Stem Cells Identified by Aldehyde Dehydrogenase 1 Expression with Resistance to Sequential Paclitaxel and Epirubicin-Based Chemotherapy for Breast Cancers</article-title><source>Clin. Cancer Res.</source><year>2009</year><volume>15</volume><fpage>4234</fpage><lpage>4241</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.CCR-08-1479</pub-id><pub-id pub-id-type="pmid">19509181</pub-id></element-citation></ref><ref id="B48-cells-08-01013"><label>48.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kang</surname><given-names>J.H.</given-names></name><name><surname>Lee</surname><given-names>S.-H.</given-names></name><name><surname>Hong</surname><given-names>D.</given-names></name><name><surname>Lee</surname><given-names>J.-S.</given-names></name><name><surname>Ahn</surname><given-names>H.-S.</given-names></name><name><surname>Ahn</surname><given-names>J.-H.</given-names></name><name><surname>Seong</surname><given-names>T.W.</given-names></name><name><surname>Lee</surname><given-names>C.-H.</given-names></name><name><surname>Jang</surname><given-names>H.</given-names></name><name><surname>Hong</surname><given-names>K.M.</given-names></name><etal></etal></person-group><article-title>Aldehyde dehydrogenase is used by cancer cells for energy metabolism</article-title><source>Exp. Mol. Med.</source><year>2016</year><volume>48</volume><fpage>e272</fpage><pub-id pub-id-type="doi">10.1038/emm.2016.103</pub-id><pub-id pub-id-type="pmid">27885254</pub-id></element-citation></ref><ref id="B49-cells-08-01013"><label>49.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Koppaka</surname><given-names>V.</given-names></name><name><surname>Thompson</surname><given-names>D.C.</given-names></name><name><surname>Chen</surname><given-names>Y.</given-names></name><name><surname>Ellermann</surname><given-names>M.</given-names></name><name><surname>Nicolaou</surname><given-names>K.C.</given-names></name><name><surname>Juvonen</surname><given-names>R.O.</given-names></name><name><surname>Petersen</surname><given-names>D.</given-names></name><name><surname>Deitrich</surname><given-names>R.A.</given-names></name><name><surname>Hurley</surname><given-names>T.D.</given-names></name><name><surname>Vasiliou</surname><given-names>V.</given-names></name></person-group><article-title>Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application</article-title><source>Pharmacol. Rev.</source><year>2012</year><volume>64</volume><fpage>520</fpage><lpage>539</lpage><pub-id pub-id-type="doi">10.1124/pr.111.005538</pub-id><pub-id pub-id-type="pmid">22544865</pub-id></element-citation></ref><ref id="B50-cells-08-01013"><label>50.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Venkatesan</surname><given-names>S.</given-names></name><name><surname>Swanton</surname><given-names>C.</given-names></name><name><surname>Taylor</surname><given-names>B.S.</given-names></name><name><surname>Costello</surname><given-names>J.F.</given-names></name></person-group><article-title>Treatment-Induced Mutagenesis and Selective Pressures Sculpt Cancer Evolution</article-title><source>Cold Spring Harb. Perspect. Med.</source><year>2017</year><volume>7</volume><fpage>a026617</fpage><pub-id pub-id-type="doi">10.1101/cshperspect.a026617</pub-id><pub-id pub-id-type="pmid">28289245</pub-id></element-citation></ref><ref id="B51-cells-08-01013"><label>51.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sever</surname><given-names>R.</given-names></name><name><surname>Brugge</surname><given-names>J.S.</given-names></name></person-group><article-title>Signal Transduction in Cancer</article-title><source>Cold Spring Harb. Perspect. Med.</source><year>2015</year><volume>5</volume><fpage>a006098</fpage><pub-id pub-id-type="doi">10.1101/cshperspect.a006098</pub-id><pub-id pub-id-type="pmid">25833940</pub-id></element-citation></ref><ref id="B52-cells-08-01013"><label>52.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Katoh</surname><given-names>M.</given-names></name></person-group><article-title>Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers</article-title><source>Clin. Sci.</source><year>2019</year><volume>133</volume><fpage>953</fpage><lpage>970</lpage><pub-id pub-id-type="doi">10.1042/CS20180845</pub-id><pub-id pub-id-type="pmid">31036756</pub-id></element-citation></ref><ref id="B53-cells-08-01013"><label>53.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rothenstein</surname><given-names>J.M.</given-names></name><name><surname>Chooback</surname><given-names>N.</given-names></name></person-group><article-title>ALK inhibitors, resistance development, clinical trials</article-title><source>Curr. Oncol.</source><year>2018</year><volume>25</volume><fpage>59</fpage><pub-id pub-id-type="doi">10.3747/co.25.3760</pub-id><pub-id pub-id-type="pmid">29507485</pub-id></element-citation></ref><ref id="B54-cells-08-01013"><label>54.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gainor</surname><given-names>J.F.</given-names></name><name><surname>Dardaei</surname><given-names>L.</given-names></name><name><surname>Yoda</surname><given-names>S.</given-names></name><name><surname>Friboulet</surname><given-names>L.</given-names></name><name><surname>Leshchiner</surname><given-names>I.</given-names></name><name><surname>Katayama</surname><given-names>R.</given-names></name><name><surname>Dagogo-Jack</surname><given-names>I.</given-names></name><name><surname>Gadgeel</surname><given-names>S.</given-names></name><name><surname>Schultz</surname><given-names>K.</given-names></name><name><surname>Singh</surname><given-names>M.</given-names></name><etal></etal></person-group><article-title>Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer</article-title><source>Cancer Discov.</source><year>2016</year><volume>6</volume><fpage>1118</fpage><lpage>1133</lpage><pub-id pub-id-type="doi">10.1158/2159-8290.CD-16-0596</pub-id><pub-id pub-id-type="pmid">27432227</pub-id></element-citation></ref><ref id="B55-cells-08-01013"><label>55.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sun</surname><given-names>D.</given-names></name><name><surname>Dalin</surname><given-names>S.</given-names></name><name><surname>Hemann</surname><given-names>M.T.</given-names></name><name><surname>Lauffenburger</surname><given-names>D.A.</given-names></name><name><surname>Zhao</surname><given-names>B.</given-names></name></person-group><article-title>Differential selective pressure alters rate of drug resistance acquisition in heterogeneous tumor populations</article-title><source>Sci. Rep.</source><year>2016</year><volume>6</volume><fpage>36198</fpage><pub-id pub-id-type="doi">10.1038/srep36198</pub-id><pub-id pub-id-type="pmid">27819268</pub-id></element-citation></ref><ref id="B56-cells-08-01013"><label>56.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Amirouchene-Angelozzi</surname><given-names>N.</given-names></name><name><surname>Swanton</surname><given-names>C.</given-names></name><name><surname>Bardelli</surname><given-names>A.</given-names></name></person-group><article-title>Tumor Evolution as a Therapeutic Target</article-title><source>Cancer Discov.</source><year>2017</year><volume>7</volume><fpage>805</fpage><lpage>817</lpage><pub-id pub-id-type="doi">10.1158/2159-8290.CD-17-0343</pub-id><pub-id pub-id-type="pmid">28729406</pub-id></element-citation></ref><ref id="B57-cells-08-01013"><label>57.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Riviere</surname><given-names>M.-K.</given-names></name><name><surname>Le Tourneau</surname><given-names>C.</given-names></name><name><surname>Paoletti</surname><given-names>X.</given-names></name><name><surname>Dubois</surname><given-names>F.</given-names></name><name><surname>Zohar</surname><given-names>S.</given-names></name></person-group><article-title>Designs of drug-combination phase I trials in oncology: a systematic review of the literature</article-title><source>Ann. Oncol.</source><year>2015</year><volume>26</volume><fpage>669</fpage><lpage>674</lpage><pub-id pub-id-type="doi">10.1093/annonc/mdu516</pub-id><pub-id pub-id-type="pmid">25403591</pub-id></element-citation></ref><ref id="B58-cells-08-01013"><label>58.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Day</surname><given-names>D.</given-names></name><name><surname>Siu</surname><given-names>L.L.</given-names></name></person-group><article-title>Approaches to modernize the combination drug development paradigm</article-title><source>Genome Med.</source><year>2016</year><volume>8</volume><fpage>115</fpage><pub-id pub-id-type="doi">10.1186/s13073-016-0369-x</pub-id><pub-id pub-id-type="pmid">27793177</pub-id></element-citation></ref><ref id="B59-cells-08-01013"><label>59.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mozgunov</surname><given-names>P.</given-names></name><name><surname>Jaki</surname><given-names>T.</given-names></name><name><surname>Paoletti</surname><given-names>X.</given-names></name></person-group><article-title>Randomized dose-escalation designs for drug combination cancer trials with immunotherapy</article-title><source>J. Biopharm. Stat.</source><year>2019</year><volume>29</volume><fpage>359</fpage><lpage>377</lpage><pub-id pub-id-type="doi">10.1080/10543406.2018.1535503</pub-id><pub-id pub-id-type="pmid">30352007</pub-id></element-citation></ref><ref id="B60-cells-08-01013"><label>60.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Paller</surname><given-names>C.J.</given-names></name><name><surname>Bradbury</surname><given-names>P.A.</given-names></name><name><surname>Ivy</surname><given-names>S.P.</given-names></name><name><surname>Seymour</surname><given-names>L.</given-names></name><name><surname>LoRusso</surname><given-names>P.M.</given-names></name><name><surname>Baker</surname><given-names>L.</given-names></name><name><surname>Rubinstein</surname><given-names>L.</given-names></name><name><surname>Huang</surname><given-names>E.</given-names></name><name><surname>Collyar</surname><given-names>D.</given-names></name><name><surname>Groshen</surname><given-names>S.</given-names></name><etal></etal></person-group><article-title>Design of Phase I Combination Trials: Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee</article-title><source>Clin. Cancer Res.</source><year>2014</year><volume>20</volume><fpage>4210</fpage><lpage>4217</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.CCR-14-0521</pub-id><pub-id pub-id-type="pmid">25125258</pub-id></element-citation></ref><ref id="B61-cells-08-01013"><label>61.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Milella</surname><given-names>M.</given-names></name><name><surname>Falcone</surname><given-names>I.</given-names></name><name><surname>Conciatori</surname><given-names>F.</given-names></name><name><surname>Cesta Incani</surname><given-names>U.</given-names></name><name><surname>Del Curatolo</surname><given-names>A.</given-names></name><name><surname>Inzerilli</surname><given-names>N.</given-names></name><name><surname>Nuzzo</surname><given-names>C.M.A.</given-names></name><name><surname>Vaccaro</surname><given-names>V.</given-names></name><name><surname>Vari</surname><given-names>S.</given-names></name><name><surname>Cognetti</surname><given-names>F.</given-names></name><etal></etal></person-group><article-title>PTEN: Multiple Functions in Human Malignant Tumors</article-title><source>Front. Oncol.</source><year>2015</year><volume>5</volume><pub-id pub-id-type="doi">10.3389/fonc.2015.00024</pub-id></element-citation></ref><ref id="B62-cells-08-01013"><label>62.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Singh</surname><given-names>S.S.</given-names></name><name><surname>Vats</surname><given-names>S.</given-names></name><name><surname>Chia</surname><given-names>A.Y.-Q.</given-names></name><name><surname>Tan</surname><given-names>T.Z.</given-names></name><name><surname>Deng</surname><given-names>S.</given-names></name><name><surname>Ong</surname><given-names>M.S.</given-names></name><name><surname>Arfuso</surname><given-names>F.</given-names></name><name><surname>Yap</surname><given-names>C.T.</given-names></name><name><surname>Goh</surname><given-names>B.C.</given-names></name><name><surname>Sethi</surname><given-names>G.</given-names></name><etal></etal></person-group><article-title>Dual role of autophagy in hallmarks of cancer</article-title><source>Oncogene</source><year>2018</year><volume>37</volume><fpage>1142</fpage><lpage>1158</lpage><pub-id pub-id-type="doi">10.1038/s41388-017-0046-6</pub-id><pub-id pub-id-type="pmid">29255248</pub-id></element-citation></ref><ref id="B63-cells-08-01013"><label>63.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Huang</surname><given-names>T.</given-names></name><name><surname>Song</surname><given-names>X.</given-names></name><name><surname>Yang</surname><given-names>Y.</given-names></name><name><surname>Wan</surname><given-names>X.</given-names></name><name><surname>Alvarez</surname><given-names>A.A.</given-names></name><name><surname>Sastry</surname><given-names>N.</given-names></name><name><surname>Feng</surname><given-names>H.</given-names></name><name><surname>Hu</surname><given-names>B.</given-names></name><name><surname>Cheng</surname><given-names>S.-Y.</given-names></name></person-group><article-title>Autophagy and Hallmarks of Cancer</article-title><source>Crit. Rev. Oncog.</source><year>2018</year><volume>23</volume><fpage>247</fpage><lpage>267</lpage><pub-id pub-id-type="doi">10.1615/CritRevOncog.2018027913</pub-id><pub-id pub-id-type="pmid">30311559</pub-id></element-citation></ref><ref id="B64-cells-08-01013"><label>64.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>Z.</given-names></name><name><surname>Trotman</surname><given-names>L.C.</given-names></name><name><surname>Shaffer</surname><given-names>D.</given-names></name><name><surname>Lin</surname><given-names>H.-K.</given-names></name><name><surname>Dotan</surname><given-names>Z.A.</given-names></name><name><surname>Niki</surname><given-names>M.</given-names></name><name><surname>Koutcher</surname><given-names>J.A.</given-names></name><name><surname>Scher</surname><given-names>H.I.</given-names></name><name><surname>Ludwig</surname><given-names>T.</given-names></name><name><surname>Gerald</surname><given-names>W.</given-names></name><etal></etal></person-group><article-title>Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis</article-title><source>Nature</source><year>2005</year><volume>436</volume><fpage>725</fpage><lpage>730</lpage><pub-id pub-id-type="doi">10.1038/nature03918</pub-id><pub-id pub-id-type="pmid">16079851</pub-id></element-citation></ref><ref id="B65-cells-08-01013"><label>65.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brandmaier</surname><given-names>A.</given-names></name><name><surname>Hou</surname><given-names>S.-Q.</given-names></name><name><surname>Shen</surname><given-names>W.H.</given-names></name></person-group><article-title>Cell Cycle Control by PTEN</article-title><source>J. Mol. Biol.</source><year>2017</year><volume>429</volume><fpage>2265</fpage><lpage>2277</lpage><pub-id pub-id-type="doi">10.1016/j.jmb.2017.06.004</pub-id><pub-id pub-id-type="pmid">28602818</pub-id></element-citation></ref><ref id="B66-cells-08-01013"><label>66.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Paramio</surname><given-names>J.M.</given-names></name><name><surname>Navarro</surname><given-names>M.</given-names></name><name><surname>Segrelles</surname><given-names>C.</given-names></name><name><surname>Gómez-Casero</surname><given-names>E.</given-names></name><name><surname>Jorcano</surname><given-names>J.L.</given-names></name></person-group><article-title>PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein</article-title><source>Oncogene</source><year>1999</year><volume>18</volume><fpage>7462</fpage><lpage>7468</lpage><pub-id pub-id-type="doi">10.1038/sj.onc.1203151</pub-id><pub-id pub-id-type="pmid">10602505</pub-id></element-citation></ref><ref id="B67-cells-08-01013"><label>67.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Otto</surname><given-names>T.</given-names></name><name><surname>Sicinski</surname><given-names>P.</given-names></name></person-group><article-title>Cell cycle proteins as promising targets in cancer therapy</article-title><source>Nat. Rev. Cancer</source><year>2017</year><pub-id pub-id-type="doi">10.1038/nrc.2016.138</pub-id></element-citation></ref><ref id="B68-cells-08-01013"><label>68.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dick</surname><given-names>F.A.</given-names></name><name><surname>Goodrich</surname><given-names>D.W.</given-names></name><name><surname>Sage</surname><given-names>J.</given-names></name><name><surname>Dyson</surname><given-names>N.J.</given-names></name></person-group><article-title>Non-canonical functions of the RB protein in cancer</article-title><source>Nat. Rev. Cancer</source><year>2018</year><volume>18</volume><fpage>442</fpage><lpage>451</lpage><pub-id pub-id-type="doi">10.1038/s41568-018-0008-5</pub-id><pub-id pub-id-type="pmid">29692417</pub-id></element-citation></ref><ref id="B69-cells-08-01013"><label>69.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Malumbres</surname><given-names>M.</given-names></name><name><surname>Barbacid</surname><given-names>M.</given-names></name></person-group><article-title>Cell cycle, CDKs and cancer: a changing paradigm</article-title><source>Nat. Rev. Cancer</source><year>2009</year><volume>9</volume><fpage>153</fpage><lpage>166</lpage><pub-id pub-id-type="doi">10.1038/nrc2602</pub-id><pub-id pub-id-type="pmid">19238148</pub-id></element-citation></ref><ref id="B70-cells-08-01013"><label>70.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sherr</surname><given-names>C.J.</given-names></name><name><surname>Beach</surname><given-names>D.</given-names></name><name><surname>Shapiro</surname><given-names>G.I.</given-names></name></person-group><article-title>Targeting CDK4 and CDK6: From Discovery to Therapy</article-title><source>Cancer Discov.</source><year>2016</year><volume>6</volume><fpage>353</fpage><lpage>367</lpage><pub-id pub-id-type="doi">10.1158/2159-8290.CD-15-0894</pub-id><pub-id pub-id-type="pmid">26658964</pub-id></element-citation></ref><ref id="B71-cells-08-01013"><label>71.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Quereda</surname><given-names>V.</given-names></name><name><surname>Porlan</surname><given-names>E.</given-names></name><name><surname>Cañamero</surname><given-names>M.</given-names></name><name><surname>Dubus</surname><given-names>P.</given-names></name><name><surname>Malumbres</surname><given-names>M.</given-names></name></person-group><article-title>An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress</article-title><source>Cell Death Differ.</source><year>2016</year><volume>23</volume><fpage>430</fpage><lpage>441</lpage><pub-id pub-id-type="doi">10.1038/cdd.2015.112</pub-id><pub-id pub-id-type="pmid">26292757</pub-id></element-citation></ref><ref id="B72-cells-08-01013"><label>72.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sanidas</surname><given-names>I.</given-names></name><name><surname>Morris</surname><given-names>R.</given-names></name><name><surname>Fella</surname><given-names>K.A.</given-names></name><name><surname>Rumde</surname><given-names>P.H.</given-names></name><name><surname>Boukhali</surname><given-names>M.</given-names></name><name><surname>Tai</surname><given-names>E.C.</given-names></name><name><surname>Ting</surname><given-names>D.T.</given-names></name><name><surname>Lawrence</surname><given-names>M.S.</given-names></name><name><surname>Haas</surname><given-names>W.</given-names></name><name><surname>Dyson</surname><given-names>N.J.</given-names></name></person-group><article-title>A Code of Mono-phosphorylation Modulates the Function of RB</article-title><source>Mol. Cell</source><year>2019</year><volume>73</volume><fpage>985</fpage><lpage>1000.e6</lpage><pub-id pub-id-type="doi">10.1016/j.molcel.2019.01.004</pub-id><pub-id pub-id-type="pmid">30711375</pub-id></element-citation></ref><ref id="B73-cells-08-01013"><label>73.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rigberg</surname><given-names>D.A.</given-names></name><name><surname>Kim</surname><given-names>F.S.</given-names></name><name><surname>Sebastian</surname><given-names>J.L.</given-names></name><name><surname>Kazanjian</surname><given-names>K.K.</given-names></name><name><surname>McFadden</surname><given-names>D.W.</given-names></name></person-group><article-title>Hypophosphorylated Retinoblastoma Protein Is Associated with G2Arrest in Esophageal Squamous Cell Carcinoma</article-title><source>J. Surg. Res.</source><year>1999</year><volume>84</volume><fpage>101</fpage><lpage>105</lpage><pub-id pub-id-type="doi">10.1006/jsre.1999.5617</pub-id><pub-id pub-id-type="pmid">10334897</pub-id></element-citation></ref><ref id="B74-cells-08-01013"><label>74.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Roesch</surname><given-names>A.</given-names></name><name><surname>Becker</surname><given-names>B.</given-names></name><name><surname>Meyer</surname><given-names>S.</given-names></name><name><surname>Hafner</surname><given-names>C.</given-names></name><name><surname>Wild</surname><given-names>P.J.</given-names></name><name><surname>Landthaler</surname><given-names>M.</given-names></name><name><surname>Vogt</surname><given-names>T.</given-names></name></person-group><article-title>Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma</article-title><source>Mod. Pathol.</source><year>2005</year><volume>18</volume><fpage>565</fpage><lpage>572</lpage><pub-id pub-id-type="doi">10.1038/modpathol.3800324</pub-id><pub-id pub-id-type="pmid">15502804</pub-id></element-citation></ref><ref id="B75-cells-08-01013"><label>75.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Senderowicz</surname><given-names>A.M.</given-names></name></person-group><article-title>Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials</article-title><source>Invest. New Drugs</source><year>1999</year><volume>17</volume><fpage>313</fpage><lpage>320</lpage><pub-id pub-id-type="doi">10.1023/A:1006353008903</pub-id><pub-id pub-id-type="pmid">10665481</pub-id></element-citation></ref><ref id="B76-cells-08-01013"><label>76.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Deep</surname><given-names>A.</given-names></name><name><surname>Marwaha</surname><given-names>R.K.</given-names></name><name><surname>Marwaha</surname><given-names>M.G.</given-names></name><name><surname>Jyoti</surname><given-names>J.</given-names></name><name><surname>Nandal</surname><given-names>R.</given-names></name><name><surname>Sharma</surname><given-names>A.K.</given-names></name></person-group><article-title>Flavopiridol as cyclin dependent kinase (CDK) inhibitor: a review</article-title><source>New J. Chem.</source><year>2018</year><volume>42</volume><fpage>18500</fpage><lpage>18507</lpage><pub-id pub-id-type="doi">10.1039/C8NJ04306J</pub-id></element-citation></ref><ref id="B77-cells-08-01013"><label>77.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Byrd</surname><given-names>J.C.</given-names></name><name><surname>Shinn</surname><given-names>C.</given-names></name><name><surname>Waselenko</surname><given-names>J.K.</given-names></name><name><surname>Fuchs</surname><given-names>E.J.</given-names></name><name><surname>Lehman</surname><given-names>T.A.</given-names></name><name><surname>Nguyen</surname><given-names>P.L.</given-names></name><name><surname>Flinn</surname><given-names>I.W.</given-names></name><name><surname>Diehl</surname><given-names>L.F.</given-names></name><name><surname>Sausville</surname><given-names>E.</given-names></name><name><surname>Grever</surname><given-names>M.R.</given-names></name></person-group><article-title>Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53</article-title><source>Blood</source><year>1998</year><volume>92</volume><fpage>3804</fpage><lpage>3816</lpage><pub-id pub-id-type="pmid">9808574</pub-id></element-citation></ref><ref id="B78-cells-08-01013"><label>78.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Asghar</surname><given-names>U.</given-names></name><name><surname>Witkiewicz</surname><given-names>A.K.</given-names></name><name><surname>Turner</surname><given-names>N.C.</given-names></name><name><surname>Knudsen</surname><given-names>E.S.</given-names></name></person-group><article-title>The history and future of targeting cyclin-dependent kinases in cancer therapy</article-title><source>Nat. Rev. Drug Discov.</source><year>2015</year><volume>14</volume><fpage>130</fpage><lpage>146</lpage><pub-id pub-id-type="doi">10.1038/nrd4504</pub-id><pub-id pub-id-type="pmid">25633797</pub-id></element-citation></ref><ref id="B79-cells-08-01013"><label>79.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Aklilu</surname><given-names>M.</given-names></name></person-group><article-title>Phase II study of flavopiridol in patients with advanced colorectal cancer</article-title><source>Ann. Oncol.</source><year>2003</year><volume>14</volume><fpage>1270</fpage><lpage>1273</lpage><pub-id pub-id-type="doi">10.1093/annonc/mdg343</pub-id><pub-id pub-id-type="pmid">12881391</pub-id></element-citation></ref><ref id="B80-cells-08-01013"><label>80.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Burdette-Radoux</surname><given-names>S.</given-names></name><name><surname>Tozer</surname><given-names>R.G.</given-names></name><name><surname>Lohmann</surname><given-names>R.C.</given-names></name><name><surname>Quirt</surname><given-names>I.</given-names></name><name><surname>Ernst</surname><given-names>D.S.</given-names></name><name><surname>Walsh</surname><given-names>W.</given-names></name><name><surname>Wainman</surname><given-names>N.</given-names></name><name><surname>Colevas</surname><given-names>A.D.</given-names></name><name><surname>Eisenhauer</surname><given-names>E.A.</given-names></name></person-group><article-title>Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma</article-title><source>Invest. New Drugs</source><year>2004</year><volume>22</volume><fpage>315</fpage><lpage>322</lpage><pub-id pub-id-type="doi">10.1023/B:DRUG.0000026258.02846.1c</pub-id><pub-id pub-id-type="pmid">15122079</pub-id></element-citation></ref><ref id="B81-cells-08-01013"><label>81.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lin</surname><given-names>T.S.</given-names></name><name><surname>Howard</surname><given-names>O.M.</given-names></name><name><surname>Neuberg</surname><given-names>D.S.</given-names></name><name><surname>Kim</surname><given-names>H.H.</given-names></name><name><surname>Shipp</surname><given-names>M.A.</given-names></name></person-group><article-title>Seventy-Two Hour Continuous Infusion Flavopiridol in Relapsed and Refractory Mantle Cell Lymphoma</article-title><source>Leuk. Lymphoma</source><year>2002</year><volume>43</volume><fpage>793</fpage><lpage>797</lpage><pub-id pub-id-type="doi">10.1080/10428190290016908</pub-id><pub-id pub-id-type="pmid">12153166</pub-id></element-citation></ref><ref id="B82-cells-08-01013"><label>82.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kouroukis</surname><given-names>C.T.</given-names></name><name><surname>Belch</surname><given-names>A.</given-names></name><name><surname>Crump</surname><given-names>M.</given-names></name><name><surname>Eisenhauer</surname><given-names>E.</given-names></name><name><surname>Gascoyne</surname><given-names>R.D.</given-names></name><name><surname>Meyer</surname><given-names>R.</given-names></name><name><surname>Lohmann</surname><given-names>R.</given-names></name><name><surname>Lopez</surname><given-names>P.</given-names></name><name><surname>Powers</surname><given-names>J.</given-names></name><name><surname>Turner</surname><given-names>R.</given-names></name><etal></etal></person-group><article-title>Flavopiridol in Untreated or Relapsed Mantle-Cell Lymphoma: Results of a Phase II Study of the National Cancer Institute of Canada Clinical Trials Group</article-title><source>J. Clin. Oncol.</source><year>2003</year><volume>21</volume><fpage>1740</fpage><lpage>1745</lpage><pub-id pub-id-type="doi">10.1200/JCO.2003.09.057</pub-id><pub-id pub-id-type="pmid">12735303</pub-id></element-citation></ref><ref id="B83-cells-08-01013"><label>83.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Finn</surname><given-names>R.S.</given-names></name><name><surname>Crown</surname><given-names>J.P.</given-names></name><name><surname>Lang</surname><given-names>I.</given-names></name><name><surname>Boer</surname><given-names>K.</given-names></name><name><surname>Bondarenko</surname><given-names>I.M.</given-names></name><name><surname>Kulyk</surname><given-names>S.O.</given-names></name><name><surname>Ettl</surname><given-names>J.</given-names></name><name><surname>Patel</surname><given-names>R.</given-names></name><name><surname>Pinter</surname><given-names>T.</given-names></name><name><surname>Schmidt</surname><given-names>M.</given-names></name><etal></etal></person-group><article-title>The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study</article-title><source>Lancet Oncol.</source><year>2015</year><volume>16</volume><fpage>25</fpage><lpage>35</lpage><pub-id pub-id-type="doi">10.1016/S1470-2045(14)71159-3</pub-id><pub-id pub-id-type="pmid">25524798</pub-id></element-citation></ref><ref id="B84-cells-08-01013"><label>84.</label><element-citation publication-type="web"><article-title>Ibrance (palbociclib) FDA Approval History - Drugs.com</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://www.drugs.com/history/ibrance.html">https://www.drugs.com/history/ibrance.html</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-08-07">(accessed on 7 August 2019)</date-in-citation></element-citation></ref><ref id="B85-cells-08-01013"><label>85.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sobhani </surname><given-names>N.</given-names></name><name><surname>D’Angelo</surname><given-names>A.</given-names></name><name><surname>Pittacolo </surname><given-names>M.</given-names></name><name><surname>Roviello </surname><given-names>G.</given-names></name><name><surname>Miccoli </surname><given-names>A.</given-names></name><name><surname>Corona</surname><given-names>S.P.</given-names></name><name><surname>Bernocchi</surname><given-names>O.</given-names></name><name><surname>Generali</surname><given-names>D.</given-names></name><name><surname>Otto</surname><given-names>T.</given-names></name></person-group><article-title>Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer</article-title><source>Cells</source><year>2019</year><volume>8</volume><elocation-id>321</elocation-id><pub-id pub-id-type="doi">10.3390/cells8040321</pub-id></element-citation></ref><ref id="B86-cells-08-01013"><label>86.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shah</surname><given-names>M.</given-names></name><name><surname>Nunes</surname><given-names>M.R.</given-names></name><name><surname>Stearns</surname><given-names>V.</given-names></name></person-group><article-title>CDK4/6 Inhibitors: Game Changers in the Management of Hormone Receptor–Positive Advanced Breast Cancer?</article-title><source>Oncology (Williston Park).</source><year>2018</year><volume>32</volume><fpage>216</fpage><lpage>222</lpage><pub-id pub-id-type="pmid">29847850</pub-id></element-citation></ref><ref id="B87-cells-08-01013"><label>87.</label><element-citation publication-type="journal"><article-title>Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer</article-title><source>N. Engl. J. Med.</source><year>2018</year><volume>379</volume><fpage>2582</fpage><pub-id pub-id-type="doi">10.1056/NEJMx180043</pub-id><pub-id pub-id-type="pmid">30586508</pub-id></element-citation></ref><ref id="B88-cells-08-01013"><label>88.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goetz</surname><given-names>M.P.</given-names></name><name><surname>Toi</surname><given-names>M.</given-names></name><name><surname>Campone</surname><given-names>M.</given-names></name><name><surname>Sohn</surname><given-names>J.</given-names></name><name><surname>Paluch-Shimon</surname><given-names>S.</given-names></name><name><surname>Huober</surname><given-names>J.</given-names></name><name><surname>Park</surname><given-names>I.H.</given-names></name><name><surname>Trédan</surname><given-names>O.</given-names></name><name><surname>Chen</surname><given-names>S.-C.</given-names></name><name><surname>Manso</surname><given-names>L.</given-names></name><etal></etal></person-group><article-title>MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer</article-title><source>J. Clin. Oncol.</source><year>2017</year><volume>35</volume><fpage>3638</fpage><lpage>3646</lpage><pub-id pub-id-type="doi">10.1200/JCO.2017.75.6155</pub-id><pub-id pub-id-type="pmid">28968163</pub-id></element-citation></ref><ref id="B89-cells-08-01013"><label>89.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Portman</surname><given-names>N.</given-names></name><name><surname>Alexandrou</surname><given-names>S.</given-names></name><name><surname>Carson</surname><given-names>E.</given-names></name><name><surname>Wang</surname><given-names>S.</given-names></name><name><surname>Lim</surname><given-names>E.</given-names></name><name><surname>Caldon</surname><given-names>C.E.</given-names></name></person-group><article-title>Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer</article-title><source>Endocr. Relat. Cancer</source><year>2019</year><fpage>R15</fpage><lpage>R30</lpage><pub-id pub-id-type="doi">10.1530/ERC-18-0317</pub-id></element-citation></ref><ref id="B90-cells-08-01013"><label>90.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jabbour-Leung</surname><given-names>N.A.</given-names></name><name><surname>Chen</surname><given-names>X.</given-names></name><name><surname>Bui</surname><given-names>T.</given-names></name><name><surname>Jiang</surname><given-names>Y.</given-names></name><name><surname>Yang</surname><given-names>D.</given-names></name><name><surname>Vijayaraghavan</surname><given-names>S.</given-names></name><name><surname>McArthur</surname><given-names>M.J.</given-names></name><name><surname>Hunt</surname><given-names>K.K.</given-names></name><name><surname>Keyomarsi</surname><given-names>K.</given-names></name></person-group><article-title>Sequential Combination Therapy of CDK Inhibition and Doxorubicin Is Synthetically Lethal in p53-Mutant Triple-Negative Breast Cancer</article-title><source>Mol. Cancer Ther.</source><year>2016</year><volume>15</volume><fpage>593</fpage><lpage>607</lpage><pub-id pub-id-type="doi">10.1158/1535-7163.MCT-15-0519</pub-id><pub-id pub-id-type="pmid">26826118</pub-id></element-citation></ref><ref id="B91-cells-08-01013"><label>91.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hanahan</surname><given-names>D.</given-names></name><name><surname>Weinberg</surname><given-names>R.A.</given-names></name></person-group><article-title>Hallmarks of Cancer: The Next Generation</article-title><source>Cell</source><year>2011</year><volume>144</volume><fpage>646</fpage><lpage>674</lpage><pub-id pub-id-type="doi">10.1016/j.cell.2011.02.013</pub-id><pub-id pub-id-type="pmid">21376230</pub-id></element-citation></ref><ref id="B92-cells-08-01013"><label>92.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Adams</surname><given-names>J.M.</given-names></name><name><surname>Cory</surname><given-names>S.</given-names></name></person-group><article-title>The BCL-2 arbiters of apoptosis and their growing role as cancer targets</article-title><source>Cell Death Differ.</source><year>2018</year><volume>25</volume><fpage>27</fpage><lpage>36</lpage><pub-id pub-id-type="doi">10.1038/cdd.2017.161</pub-id><pub-id pub-id-type="pmid">29099483</pub-id></element-citation></ref><ref id="B93-cells-08-01013"><label>93.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stegh</surname><given-names>A.H.</given-names></name></person-group><article-title>Targeting the p53 signaling pathway in cancer therapy—The promises, challenges and perils</article-title><source>Expert Opin. Ther. Targets</source><year>2012</year><volume>16</volume><fpage>67</fpage><lpage>83</lpage><pub-id pub-id-type="doi">10.1517/14728222.2011.643299</pub-id><pub-id pub-id-type="pmid">22239435</pub-id></element-citation></ref><ref id="B94-cells-08-01013"><label>94.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Galluzzi</surname><given-names>L.</given-names></name><name><surname>Baehrecke</surname><given-names>E.H.</given-names></name><name><surname>Ballabio</surname><given-names>A.</given-names></name><name><surname>Boya</surname><given-names>P.</given-names></name><name><surname>Bravo-San Pedro</surname><given-names>J.M.</given-names></name><name><surname>Cecconi</surname><given-names>F.</given-names></name><name><surname>Choi</surname><given-names>A.M.</given-names></name><name><surname>Chu</surname><given-names>C.T.</given-names></name><name><surname>Codogno</surname><given-names>P.</given-names></name><name><surname>Colombo</surname><given-names>M.I.</given-names></name><etal></etal></person-group><article-title>Molecular definitions of autophagy and related processes</article-title><source>EMBO J.</source><year>2017</year><volume>36</volume><fpage>1811</fpage><lpage>1836</lpage><pub-id pub-id-type="doi">10.15252/embj.201796697</pub-id><pub-id pub-id-type="pmid">28596378</pub-id></element-citation></ref><ref id="B95-cells-08-01013"><label>95.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vessoni</surname><given-names>A.T.</given-names></name><name><surname>Filippi-Chiela</surname><given-names>E.C.</given-names></name><name><surname>Menck</surname><given-names>C.F.</given-names></name><name><surname>Lenz</surname><given-names>G.</given-names></name></person-group><article-title>Autophagy and genomic integrity</article-title><source>Cell Death Differ.</source><year>2013</year><volume>20</volume><fpage>1444</fpage><lpage>1454</lpage><pub-id pub-id-type="doi">10.1038/cdd.2013.103</pub-id><pub-id pub-id-type="pmid">23933813</pub-id></element-citation></ref><ref id="B96-cells-08-01013"><label>96.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hewitt</surname><given-names>G.</given-names></name><name><surname>Korolchuk</surname><given-names>V.I.</given-names></name></person-group><article-title>Repair, Reuse, Recycle: The Expanding Role of Autophagy in Genome Maintenance</article-title><source>Trends Cell Biol.</source><year>2017</year><volume>27</volume><fpage>340</fpage><lpage>351</lpage><pub-id pub-id-type="doi">10.1016/j.tcb.2016.11.011</pub-id><pub-id pub-id-type="pmid">28011061</pub-id></element-citation></ref><ref id="B97-cells-08-01013"><label>97.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kroemer</surname><given-names>G.</given-names></name><name><surname>Levine</surname><given-names>B.</given-names></name></person-group><article-title>Autophagic cell death: the story of a misnomer</article-title><source>Nat. Rev. Mol. Cell Biol.</source><year>2008</year><volume>9</volume><fpage>1004</fpage><lpage>1010</lpage><pub-id pub-id-type="doi">10.1038/nrm2529</pub-id><pub-id pub-id-type="pmid">18971948</pub-id></element-citation></ref><ref id="B98-cells-08-01013"><label>98.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kondapuram</surname><given-names>S.K.</given-names></name><name><surname>Sarvagalla</surname><given-names>S.</given-names></name><name><surname>Coumar</surname><given-names>M.S.</given-names></name></person-group><article-title>Targeting autophagy with small molecules for cancer therapy</article-title><source>J. Cancer Metastasis Treat.</source><year>2019</year><volume>2019</volume><pub-id pub-id-type="doi">10.20517/2394-4722.2018.105</pub-id></element-citation></ref><ref id="B99-cells-08-01013"><label>99.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Delou</surname><given-names>J.M.A.</given-names></name><name><surname>Biasoli</surname><given-names>D.</given-names></name><name><surname>Borges</surname><given-names>H.L.</given-names></name></person-group><article-title>The Complex Link between Apoptosis and Autophagy: a Promising New Role for RB</article-title><source>An. Acad. Bras. Cienc.</source><year>2016</year><volume>88</volume><fpage>2257</fpage><lpage>2275</lpage><pub-id pub-id-type="doi">10.1590/0001-3765201620160127</pub-id><pub-id pub-id-type="pmid">27991962</pub-id></element-citation></ref><ref id="B100-cells-08-01013"><label>100.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morselli</surname><given-names>E.</given-names></name><name><surname>Galluzzi</surname><given-names>L.</given-names></name><name><surname>Kepp</surname><given-names>O.</given-names></name><name><surname>Vicencio</surname><given-names>J.-M.</given-names></name><name><surname>Criollo</surname><given-names>A.</given-names></name><name><surname>Maiuri</surname><given-names>M.C.</given-names></name><name><surname>Kroemer</surname><given-names>G.</given-names></name></person-group><article-title>Anti- and pro-tumor functions of autophagy</article-title><source>Biochim. Biophys. Acta - Mol. Cell Res.</source><year>2009</year><volume>1793</volume><fpage>1524</fpage><lpage>1532</lpage><pub-id pub-id-type="doi">10.1016/j.bbamcr.2009.01.006</pub-id></element-citation></ref><ref id="B101-cells-08-01013"><label>101.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shang</surname><given-names>L.</given-names></name><name><surname>Wang</surname><given-names>X.</given-names></name></person-group><article-title>AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation</article-title><source>Autophagy</source><year>2011</year><volume>7</volume><fpage>924</fpage><lpage>926</lpage><pub-id pub-id-type="doi">10.4161/auto.7.8.15860</pub-id><pub-id pub-id-type="pmid">21521945</pub-id></element-citation></ref><ref id="B102-cells-08-01013"><label>102.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ouyang</surname><given-names>L.</given-names></name><name><surname>Shi</surname><given-names>Z.</given-names></name><name><surname>Zhao</surname><given-names>S.</given-names></name><name><surname>Wang</surname><given-names>F.-T.</given-names></name><name><surname>Zhou</surname><given-names>T.-T.</given-names></name><name><surname>Liu</surname><given-names>B.</given-names></name><name><surname>Bao</surname><given-names>J.-K.</given-names></name></person-group><article-title>Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis</article-title><source>Cell Prolif.</source><year>2012</year><volume>45</volume><fpage>487</fpage><lpage>498</lpage><pub-id pub-id-type="doi">10.1111/j.1365-2184.2012.00845.x</pub-id><pub-id pub-id-type="pmid">23030059</pub-id></element-citation></ref><ref id="B103-cells-08-01013"><label>103.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Biasoli</surname><given-names>D.</given-names></name><name><surname>Kahn</surname><given-names>S.A.</given-names></name><name><surname>Cornélio</surname><given-names>T.A.</given-names></name><name><surname>Furtado</surname><given-names>M.</given-names></name><name><surname>Campanati</surname><given-names>L.</given-names></name><name><surname>Chneiweiss</surname><given-names>H.</given-names></name><name><surname>Moura-Neto</surname><given-names>V.</given-names></name><name><surname>Borges</surname><given-names>H.L.</given-names></name></person-group><article-title>Retinoblastoma protein regulates the crosstalk between autophagy and apoptosis, and favors glioblastoma resistance to etoposide</article-title><source>Cell Death Dis.</source><year>2013</year><volume>4</volume><fpage>e767</fpage><pub-id pub-id-type="doi">10.1038/cddis.2013.283</pub-id><pub-id pub-id-type="pmid">23949216</pub-id></element-citation></ref><ref id="B104-cells-08-01013"><label>104.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Han</surname><given-names>J.</given-names></name><name><surname>Soletti</surname><given-names>R.C.</given-names></name><name><surname>Sadarangani</surname><given-names>A.</given-names></name><name><surname>Sridevi</surname><given-names>P.</given-names></name><name><surname>Ramirez</surname><given-names>M.E.</given-names></name><name><surname>Eckmann</surname><given-names>L.</given-names></name><name><surname>Borges</surname><given-names>H.L.</given-names></name><name><surname>Wang</surname><given-names>J.Y.J.</given-names></name></person-group><article-title>Nuclear Expression of β-Catenin Promotes RB Stability and Resistance to TNF-Induced Apoptosis in Colon Cancer Cells</article-title><source>Mol. Cancer Res.</source><year>2013</year><volume>11</volume><fpage>207</fpage><lpage>218</lpage><pub-id pub-id-type="doi">10.1158/1541-7786.MCR-12-0670</pub-id><pub-id pub-id-type="pmid">23339186</pub-id></element-citation></ref><ref id="B105-cells-08-01013"><label>105.</label><element-citation publication-type="gov"><article-title>LEE011 Plus Everolimus in Patients With Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02985125?term=NCT02985125&rank=1">https://clinicaltrials.gov/ct2/show/NCT02985125?term=NCT02985125&rank=1</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B106-cells-08-01013"><label>106.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Michaloglou</surname><given-names>C.</given-names></name><name><surname>Crafter</surname><given-names>C.</given-names></name><name><surname>Siersbaek</surname><given-names>R.</given-names></name><name><surname>Delpuech</surname><given-names>O.</given-names></name><name><surname>Curwen</surname><given-names>J.O.</given-names></name><name><surname>Carnevalli</surname><given-names>L.S.</given-names></name><name><surname>Staniszewska</surname><given-names>A.D.</given-names></name><name><surname>Polanska</surname><given-names>U.M.</given-names></name><name><surname>Cheraghchi-Bashi</surname><given-names>A.</given-names></name><name><surname>Lawson</surname><given-names>M.</given-names></name><etal></etal></person-group><article-title>Combined Inhibition of mTOR and CDK4/6 Is Required for Optimal Blockade of E2F Function and Long-term Growth Inhibition in Estrogen Receptor–positive Breast Cancer</article-title><source>Mol. Cancer Ther.</source><year>2018</year><volume>17</volume><fpage>908</fpage><lpage>920</lpage><pub-id pub-id-type="doi">10.1158/1535-7163.MCT-17-0537</pub-id><pub-id pub-id-type="pmid">29483206</pub-id></element-citation></ref><ref id="B107-cells-08-01013"><label>107.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berrak</surname><given-names>O.</given-names></name><name><surname>Arisan</surname><given-names>E.D.</given-names></name><name><surname>Obakan-Yerlikaya</surname><given-names>P.</given-names></name><name><surname>Coker-Gürkan</surname><given-names>A.</given-names></name><name><surname>Palavan-Unsal</surname><given-names>N.</given-names></name></person-group><article-title>mTOR is a fine tuning molecule in CDK inhibitors-induced distinct cell death mechanisms via PI3K/AKT/mTOR signaling axis in prostate cancer cells</article-title><source>Apoptosis</source><year>2016</year><volume>21</volume><fpage>1158</fpage><lpage>1178</lpage><pub-id pub-id-type="doi">10.1007/s10495-016-1275-9</pub-id><pub-id pub-id-type="pmid">27484210</pub-id></element-citation></ref><ref id="B108-cells-08-01013"><label>108.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname><given-names>G.</given-names></name><name><surname>Nowsheen</surname><given-names>S.</given-names></name><name><surname>Aziz</surname><given-names>K.</given-names></name><name><surname>Georgakilas</surname><given-names>A.G.</given-names></name></person-group><article-title>Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs</article-title><source>Pharmacol. Ther.</source><year>2013</year><volume>139</volume><fpage>392</fpage><lpage>404</lpage><pub-id pub-id-type="doi">10.1016/j.pharmthera.2013.05.005</pub-id><pub-id pub-id-type="pmid">23711794</pub-id></element-citation></ref><ref id="B109-cells-08-01013"><label>109.</label><element-citation publication-type="gov"><article-title>Bosutinib in Combination With Pemetrexed in Patients With Selected Metastatic Solid Tumors - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03023319?term=bosutinib&draw=2&rank=2">https://clinicaltrials.gov/ct2/show/NCT03023319?term=bosutinib&draw=2&rank=2</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-15">(accessed on 15 July 2019)</date-in-citation></element-citation></ref><ref id="B110-cells-08-01013"><label>110.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Secord</surname><given-names>A.A.</given-names></name><name><surname>Teoh</surname><given-names>D.K.</given-names></name><name><surname>Barry</surname><given-names>W.T.</given-names></name><name><surname>Yu</surname><given-names>M.</given-names></name><name><surname>Broadwater</surname><given-names>G.</given-names></name><name><surname>Havrilesky</surname><given-names>L.J.</given-names></name><name><surname>Lee</surname><given-names>P.S.</given-names></name><name><surname>Berchuck</surname><given-names>A.</given-names></name><name><surname>Lancaster</surname><given-names>J.</given-names></name><name><surname>Wenham</surname><given-names>R.M.</given-names></name></person-group><article-title>A Phase I Trial of Dasatinib, an Src-Family Kinase Inhibitor, in Combination with Paclitaxel and Carboplatin in Patients with Advanced or Recurrent Ovarian Cancer</article-title><source>Clin. Cancer Res.</source><year>2012</year><volume>18</volume><fpage>5489</fpage><lpage>5498</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.CCR-12-0507</pub-id><pub-id pub-id-type="pmid">22837181</pub-id></element-citation></ref><ref id="B111-cells-08-01013"><label>111.</label><element-citation publication-type="gov"><article-title>Azacitidine and Venetoclax as Induction Therapy With Venetoclax Maintenance in the Elderly With AML</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT03466294">https://clinicaltrials.gov/show/NCT03466294</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B112-cells-08-01013"><label>112.</label><element-citation publication-type="gov"><article-title>Venetoclax and Chemotherapy as Frontline Therapy in Older Patients and Patients With Relapsed/Refractory ALL</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT03319901">https://clinicaltrials.gov/show/NCT03319901</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B113-cells-08-01013"><label>113.</label><element-citation publication-type="gov"><article-title>A Study of Abemaciclib (LY2835219) in Combination With Another Anti-cancer Drug in Participants With Lung Cancer (NSCLC)</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT02079636">https://clinicaltrials.gov/show/NCT02079636</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B114-cells-08-01013"><label>114.</label><element-citation publication-type="gov"><article-title>INdividualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT)</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT02977780">https://clinicaltrials.gov/show/NCT02977780</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B115-cells-08-01013"><label>115.</label><element-citation publication-type="gov"><article-title>Phase II Trial Evaluating the Efficacy of Palbociclib in Combination With Carboplatin for the Treatment of Unresectable Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT03194373">https://clinicaltrials.gov/show/NCT03194373</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B116-cells-08-01013"><label>116.</label><element-citation publication-type="gov"><article-title>Dose-Escalation Study Of Palbociclib + Nab-Paclitaxel In mPDAC</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT02501902">https://clinicaltrials.gov/show/NCT02501902</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B117-cells-08-01013"><label>117.</label><element-citation publication-type="gov"><article-title>Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT03709680">https://clinicaltrials.gov/show/NCT03709680</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B118-cells-08-01013"><label>118.</label><element-citation publication-type="gov"><article-title>LEE011 (Ribociclib) in Combination With Docetaxel Plus Prednisone in mCRPC</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT02494921">https://clinicaltrials.gov/show/NCT02494921</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B119-cells-08-01013"><label>119.</label><element-citation publication-type="gov"><article-title>SJDAWN: St. Jude Children’s Research Hospital Phase 1 Study Evaluating Molecularly-Driven Doublet Therapies for Children and Young Adults With Recurrent Brain Tumors</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT03434262">https://clinicaltrials.gov/show/NCT03434262</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B120-cells-08-01013"><label>120.</label><element-citation publication-type="gov"><article-title>Ribociclib (Ribociclib (LEE-011)) With Platinum-based Chemotherapy in Recurrent Platinum Sensitive Ovarian Cancer</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT03056833">https://clinicaltrials.gov/show/NCT03056833</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B121-cells-08-01013"><label>121.</label><element-citation publication-type="gov"><article-title>Niraparib and Temozolomide in Treating Patients With Extensive-Stage Small Cell Lung Cancer With a Complete or Partial Response to Platinum-Based First-Line Chemotherapy</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT03830918">https://clinicaltrials.gov/show/NCT03830918</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B122-cells-08-01013"><label>122.</label><element-citation publication-type="gov"><article-title>Olaparib Dose Escalating Trial + Concurrent RT With or Without Cisplatin in Locally Advanced NSCLC</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT01562210">https://clinicaltrials.gov/show/NCT01562210</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B123-cells-08-01013"><label>123.</label><element-citation publication-type="gov"><article-title>Rucaparib and Irinotecan in Cancers With Mutations in DNA Repair</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/show/NCT03318445">https://clinicaltrials.gov/show/NCT03318445</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-06-15">(accessed on 15 June 2019)</date-in-citation></element-citation></ref><ref id="B124-cells-08-01013"><label>124.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berlin</surname><given-names>J.</given-names></name><name><surname>Ramanathan</surname><given-names>R.K.</given-names></name><name><surname>Strickler</surname><given-names>J.H.</given-names></name><name><surname>Subramaniam</surname><given-names>D.S.</given-names></name><name><surname>Marshall</surname><given-names>J.</given-names></name><name><surname>Kang</surname><given-names>Y.-K.</given-names></name><name><surname>Hetman</surname><given-names>R.</given-names></name><name><surname>Dudley</surname><given-names>M.W.</given-names></name><name><surname>Zeng</surname><given-names>J.</given-names></name><name><surname>Nickner</surname><given-names>C.</given-names></name><etal></etal></person-group><article-title>A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours</article-title><source>Br. J. Cancer</source><year>2018</year><volume>118</volume><fpage>938</fpage><lpage>946</lpage><pub-id pub-id-type="doi">10.1038/s41416-018-0003-3</pub-id><pub-id pub-id-type="pmid">29527010</pub-id></element-citation></ref><ref id="B125-cells-08-01013"><label>125.</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Murai</surname><given-names>J.</given-names></name><name><surname>Pommier</surname><given-names>Y.</given-names></name></person-group><article-title>Classification of PARP Inhibitors Based on PARP Trapping and Catalytic Inhibition, and Rationale for Combinations with Topoisomerase I Inhibitors and Alkylating Agents</article-title><source>PARP Inhibitors for Cancer Therapy</source><publisher-name>Springer</publisher-name><publisher-loc>Berlin, Germany</publisher-loc><year>2015</year><fpage>261</fpage><lpage>274</lpage></element-citation></ref><ref id="B126-cells-08-01013"><label>126.</label><element-citation publication-type="gov"><article-title>Veliparib and Temozolomide in Treating Patients With Acute Leukemia - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01139970">https://clinicaltrials.gov/ct2/show/NCT01139970</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-08-01">(accessed on 1 August 2019)</date-in-citation></element-citation></ref><ref id="B127-cells-08-01013"><label>127.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pishvaian</surname><given-names>M.J.</given-names></name><name><surname>Slack</surname><given-names>R.S.</given-names></name><name><surname>Jiang</surname><given-names>W.</given-names></name><name><surname>He</surname><given-names>A.R.</given-names></name><name><surname>Hwang</surname><given-names>J.J.</given-names></name><name><surname>Hankin</surname><given-names>A.</given-names></name><name><surname>Dorsch-Vogel</surname><given-names>K.</given-names></name><name><surname>Kukadiya</surname><given-names>D.</given-names></name><name><surname>Weiner</surname><given-names>L.M.</given-names></name><name><surname>Marshall</surname><given-names>J.L.</given-names></name><etal></etal></person-group><article-title>A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer</article-title><source>Cancer</source><year>2018</year><volume>124</volume><fpage>2337</fpage><lpage>2346</lpage><pub-id pub-id-type="doi">10.1002/cncr.31309</pub-id><pub-id pub-id-type="pmid">29579325</pub-id></element-citation></ref><ref id="B128-cells-08-01013"><label>128.</label><element-citation publication-type="gov"><article-title>Veliparib and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://www.clinicaltrials.gov/ct2/show/NCT00588991?term=veliparib%2C+topotecan&rank=2">https://www.clinicaltrials.gov/ct2/show/NCT00588991?term=veliparib%2C+topotecan&rank=2</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B129-cells-08-01013"><label>129.</label><element-citation publication-type="gov"><article-title>Study of Folfiri/Cetuximab in FcGammaRIIIa V/V Stage IV Colorectal Cancer Patients - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03874026?term=cetuximab&draw=2&rank=15">https://clinicaltrials.gov/ct2/show/NCT03874026?term=cetuximab&draw=2&rank=15</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B130-cells-08-01013"><label>130.</label><element-citation publication-type="gov"><article-title>Neoadjuvant Chemotherapy Combined With Cetuximab for EGFR Wild Type Locally Advanced Rectal Cancer - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03391843?term=cetuximab&draw=2&rank=4">https://clinicaltrials.gov/ct2/show/NCT03391843?term=cetuximab&draw=2&rank=4</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B131-cells-08-01013"><label>131.</label><element-citation publication-type="gov"><article-title>Necitumumab in the Neoadjuvant Setting With Gemcitabine in Surgically Resectable - 14X-US-I001 - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03574818?term=necitumumab&draw=2&rank=1">https://clinicaltrials.gov/ct2/show/NCT03574818?term=necitumumab&draw=2&rank=1</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B132-cells-08-01013"><label>132.</label><element-citation publication-type="gov"><article-title>A Study of Perioperative Chemotherapy Plus Panitumumab in Patients With Colorectal Cancer Liver Metastases - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01260415?term=panitumumab&draw=3">https://clinicaltrials.gov/ct2/show/NCT01260415?term=panitumumab&draw=3</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B133-cells-08-01013"><label>133.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yoshino</surname><given-names>T.</given-names></name><name><surname>Uetake</surname><given-names>H.</given-names></name><name><surname>Tsuchihara</surname><given-names>K.</given-names></name><name><surname>Shitara</surname><given-names>K.</given-names></name><name><surname>Yamazaki</surname><given-names>K.</given-names></name><name><surname>Oki</surname><given-names>E.</given-names></name><name><surname>Sato</surname><given-names>T.</given-names></name><name><surname>Naitoh</surname><given-names>T.</given-names></name><name><surname>Komatsu</surname><given-names>Y.</given-names></name><name><surname>Kato</surname><given-names>T.</given-names></name><etal></etal></person-group><article-title>Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS ( KRAS/NRAS ) Wild-type, Metastatic Colorectal Cancer</article-title><source>Clin. Colorectal Cancer</source><year>2017</year><volume>16</volume><fpage>158</fpage><lpage>163</lpage><pub-id pub-id-type="doi">10.1016/j.clcc.2017.01.001</pub-id><pub-id pub-id-type="pmid">28237539</pub-id></element-citation></ref><ref id="B134-cells-08-01013"><label>134.</label><element-citation publication-type="gov"><article-title>DAPHNe: Paclitaxel/Trastuzumab/Pertuzumab in HER2-Positive BC - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03716180?term=pertuzumab&rank=7">https://clinicaltrials.gov/ct2/show/NCT03716180?term=pertuzumab&rank=7</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B135-cells-08-01013"><label>135.</label><element-citation publication-type="gov"><article-title>Copanlisib (BAY 80-6946) in Combination With Gemcitabine and Cisplatin in Advanced Cholangiocarcinoma - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02631590?term=copanlisib&draw=5&rank=32">https://clinicaltrials.gov/ct2/show/NCT02631590?term=copanlisib&draw=5&rank=32</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B136-cells-08-01013"><label>136.</label><element-citation publication-type="gov"><article-title>A Phase 1b/2 Study of IPI-145 Plus FCR in Previously Untreated, Younger Patients With CLL - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02158091?term=duvelisib&draw=4&rank=28">https://clinicaltrials.gov/ct2/show/NCT02158091?term=duvelisib&draw=4&rank=28</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B137-cells-08-01013"><label>137.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hauke</surname><given-names>R.J.</given-names></name><name><surname>Infante</surname><given-names>J.R.</given-names></name><name><surname>Rubin</surname><given-names>M.S.</given-names></name><name><surname>Shih</surname><given-names>K.C.</given-names></name><name><surname>Arrowsmith</surname><given-names>E.R.</given-names></name><name><surname>Hainsworth</surname><given-names>J.D.</given-names></name></person-group><article-title>Everolimus in combination with paclitaxel and carboplatin in patients with metastatic melanoma: a phase II trial of the Sarah Cannon Research Institute Oncology Research Consortium</article-title><source>Melanoma Res.</source><year>2013</year><volume>23</volume><fpage>468</fpage><lpage>473</lpage><pub-id pub-id-type="doi">10.1097/CMR.0000000000000014</pub-id><pub-id pub-id-type="pmid">23969699</pub-id></element-citation></ref><ref id="B138-cells-08-01013"><label>138.</label><element-citation publication-type="gov"><article-title>Everolimus With and Without Temozolomide in Adult Low Grade Glioma - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02023905?term=temozolomide%2C+pi3k&rank=1">https://clinicaltrials.gov/ct2/show/NCT02023905?term=temozolomide%2C+pi3k&rank=1</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B139-cells-08-01013"><label>139.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zelenetz</surname><given-names>A.D.</given-names></name><name><surname>Barrientos</surname><given-names>J.C.</given-names></name><name><surname>Brown</surname><given-names>J.R.</given-names></name><name><surname>Coiffier</surname><given-names>B.</given-names></name><name><surname>Delgado</surname><given-names>J.</given-names></name><name><surname>Egyed</surname><given-names>M.</given-names></name><name><surname>Ghia</surname><given-names>P.</given-names></name><name><surname>Illés</surname><given-names>Á.</given-names></name><name><surname>Jurczak</surname><given-names>W.</given-names></name><name><surname>Marlton</surname><given-names>P.</given-names></name><etal></etal></person-group><article-title>Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial</article-title><source>Lancet Oncol.</source><year>2017</year><volume>18</volume><fpage>297</fpage><lpage>311</lpage><pub-id pub-id-type="doi">10.1016/S1470-2045(16)30671-4</pub-id><pub-id pub-id-type="pmid">28139405</pub-id></element-citation></ref><ref id="B140-cells-08-01013"><label>140.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dunn</surname><given-names>L.A.</given-names></name><name><surname>Fury</surname><given-names>M.G.</given-names></name><name><surname>Xiao</surname><given-names>H.</given-names></name><name><surname>Baxi</surname><given-names>S.S.</given-names></name><name><surname>Sherman</surname><given-names>E.J.</given-names></name><name><surname>Korte</surname><given-names>S.</given-names></name><name><surname>Pfister</surname><given-names>C.</given-names></name><name><surname>Haque</surname><given-names>S.</given-names></name><name><surname>Katabi</surname><given-names>N.</given-names></name><name><surname>Ho</surname><given-names>A.L.</given-names></name><etal></etal></person-group><article-title>A phase II study of temsirolimus added to low-dose weekly carboplatin and paclitaxel for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)</article-title><source>Ann. Oncol.</source><year>2017</year><volume>28</volume><fpage>2533</fpage><lpage>2538</lpage><pub-id pub-id-type="doi">10.1093/annonc/mdx346</pub-id><pub-id pub-id-type="pmid">28961834</pub-id></element-citation></ref><ref id="B141-cells-08-01013"><label>141.</label><element-citation publication-type="gov"><article-title>A Study of Avastin (Bevacizumab) and Xeloda (Capecitabine) in Patients With Advanced or Metastatic Liver Cancer - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://www.clinicaltrials.gov/ct2/show/NCT02013830?term=02013830&rank=1">https://www.clinicaltrials.gov/ct2/show/NCT02013830?term=02013830&rank=1</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B142-cells-08-01013"><label>142.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McWilliams</surname><given-names>R.R.</given-names></name><name><surname>Allred</surname><given-names>J.B.</given-names></name><name><surname>Slostad</surname><given-names>J.A.</given-names></name><name><surname>Katipamula</surname><given-names>R.</given-names></name><name><surname>Dronca</surname><given-names>R.S.</given-names></name><name><surname>Rumilla</surname><given-names>K.M.</given-names></name><name><surname>Erickson</surname><given-names>L.A.</given-names></name><name><surname>Bryce</surname><given-names>A.H.</given-names></name><name><surname>Joseph</surname><given-names>R.W.</given-names></name><name><surname>Kottschade</surname><given-names>L.A.</given-names></name><etal></etal></person-group><article-title>NCCTG N0879 (Alliance): A randomized phase 2 cooperative group trial of carboplatin, paclitaxel, and bevacizumab ± everolimus for metastatic melanoma</article-title><source>Cancer</source><year>2018</year><volume>124</volume><fpage>537</fpage><lpage>545</lpage><pub-id pub-id-type="doi">10.1002/cncr.31072</pub-id><pub-id pub-id-type="pmid">29044496</pub-id></element-citation></ref><ref id="B143-cells-08-01013"><label>143.</label><element-citation publication-type="gov"><article-title>Onvansertib in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients With a Kras Mutation - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03829410?term=bevacizumab%2C+FOLFIRI&rank=3">https://clinicaltrials.gov/ct2/show/NCT03829410?term=bevacizumab%2C+FOLFIRI&rank=3</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B144-cells-08-01013"><label>144.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Van den Bent</surname><given-names>M.J.</given-names></name><name><surname>Klein</surname><given-names>M.</given-names></name><name><surname>Smits</surname><given-names>M.</given-names></name><name><surname>Reijneveld</surname><given-names>J.C.</given-names></name><name><surname>French</surname><given-names>P.J.</given-names></name><name><surname>Clement</surname><given-names>P.</given-names></name><name><surname>de Vos</surname><given-names>F.Y.F.</given-names></name><name><surname>Wick</surname><given-names>A.</given-names></name><name><surname>Mulholland</surname><given-names>P.J.</given-names></name><name><surname>Taphoorn</surname><given-names>M.J.B.</given-names></name><etal></etal></person-group><article-title>Bevacizumab and temozolomide in patients with first recurrence of WHO grade II and III glioma, without 1p/19q co-deletion (TAVAREC): A randomised controlled phase 2 EORTC trial</article-title><source>Lancet Oncol.</source><year>2018</year><volume>19</volume><fpage>1170</fpage><lpage>1179</lpage><pub-id pub-id-type="doi">10.1016/S1470-2045(18)30362-0</pub-id><pub-id pub-id-type="pmid">30115593</pub-id></element-citation></ref><ref id="B145-cells-08-01013"><label>145.</label><element-citation publication-type="gov"><article-title>Lenvatinib and Weekly Paclitaxel for Patients With Recurrent Endometrial or Ovarian Cancer - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02788708?term=lenvatinib&rank=10">https://clinicaltrials.gov/ct2/show/NCT02788708?term=lenvatinib&rank=10</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B146-cells-08-01013"><label>146.</label><element-citation publication-type="gov"><article-title>Ramucirumab Plus FOLFIRI Versus Ramucirumab Plus Paclitaxel in Patients With Advanced or Metastatic Gastric Cancer, Who Failed One Prior Line of Palliative Chemotherapy - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03081143?term=ramucirumab%2C+folfiri&rank=2">https://clinicaltrials.gov/ct2/show/NCT03081143?term=ramucirumab%2C+folfiri&rank=2</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B147-cells-08-01013"><label>147.</label><element-citation publication-type="gov"><article-title>Regorafenib Combined With Irinotecan as Second-line in Patients With Metastatic Gastro-oesophageal Adenocarcinomas - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03722108?term=regorafenib&draw=2&rank=6">https://clinicaltrials.gov/ct2/show/NCT03722108?term=regorafenib&draw=2&rank=6</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B148-cells-08-01013"><label>148.</label><element-citation publication-type="gov"><article-title>Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors With Sorafenib in Combination With Irinotecan - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02747537?term=irinotecan%2C+vegfr&rank=3">https://clinicaltrials.gov/ct2/show/NCT02747537?term=irinotecan%2C+vegfr&rank=3</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B149-cells-08-01013"><label>149.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Santoro</surname><given-names>A.</given-names></name><name><surname>Su</surname><given-names>W.-C.</given-names></name><name><surname>Navarro</surname><given-names>A.</given-names></name><name><surname>Simonelli</surname><given-names>M.</given-names></name><name><surname>Yang</surname><given-names>J.C.-H.</given-names></name><name><surname>Ardizzoni</surname><given-names>A.</given-names></name><name><surname>Barlesi</surname><given-names>F.</given-names></name><name><surname>Kang</surname><given-names>J.H.</given-names></name><name><surname>Didominick</surname><given-names>S.</given-names></name><name><surname>Abdelhady</surname><given-names>A.</given-names></name><etal></etal></person-group><article-title>1392PDose-determination results from a phase Ib/II study of ceritinib (CER) + ribociclib (RIB) in ALK-positive (ALK+) non-small cell lung cancer (NSCLC)</article-title><source>Ann. Oncol.</source><year>2018</year><volume>29</volume><pub-id pub-id-type="doi">10.1093/annonc/mdy292.015</pub-id></element-citation></ref><ref id="B150-cells-08-01013"><label>150.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wood</surname><given-names>A.C.</given-names></name><name><surname>Krytska</surname><given-names>K.</given-names></name><name><surname>Ryles</surname><given-names>H.T.</given-names></name><name><surname>Infarinato</surname><given-names>N.R.</given-names></name><name><surname>Sano</surname><given-names>R.</given-names></name><name><surname>Hansel</surname><given-names>T.D.</given-names></name><name><surname>Hart</surname><given-names>L.S.</given-names></name><name><surname>King</surname><given-names>F.J.</given-names></name><name><surname>Smith</surname><given-names>T.R.</given-names></name><name><surname>Ainscow</surname><given-names>E.</given-names></name><etal></etal></person-group><article-title>Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma</article-title><source>Clin. Cancer Res.</source><year>2017</year><volume>23</volume><fpage>2856</fpage><lpage>2868</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.CCR-16-1114</pub-id><pub-id pub-id-type="pmid">27986745</pub-id></element-citation></ref><ref id="B151-cells-08-01013"><label>151.</label><element-citation publication-type="gov"><article-title>Next Generation Personalized Neuroblastoma Therapy (NEPENTHE)</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02780128?term=ceritinib%2C+ribociclib&rank=2">https://clinicaltrials.gov/ct2/show/NCT02780128?term=ceritinib%2C+ribociclib&rank=2</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B152-cells-08-01013"><label>152.</label><element-citation publication-type="gov"><article-title>Crizotinib in Combination With Enzalutamide in Metastatic Castration-resistant Prostate Cancer - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02207504?term=crizotinib&recrs=de&rank=4">https://clinicaltrials.gov/ct2/show/NCT02207504?term=crizotinib&recrs=de&rank=4</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B153-cells-08-01013"><label>153.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tripathi</surname><given-names>A.</given-names></name><name><surname>Supko</surname><given-names>J.G.</given-names></name><name><surname>Gray</surname><given-names>K.P.</given-names></name><name><surname>Melnick</surname><given-names>Z.</given-names></name><name><surname>Taplin</surname><given-names>M.-E.</given-names></name><name><surname>Choudhury</surname><given-names>A.D.</given-names></name><name><surname>Pomerantz</surname><given-names>M.</given-names></name><name><surname>Bellmunt</surname><given-names>J.</given-names></name><name><surname>Yu</surname><given-names>C.</given-names></name><name><surname>Sun</surname><given-names>Z.</given-names></name><etal></etal></person-group><article-title>852PPharmacokinetic (PK) analysis of concurrent administration of enzalutamide (enza) and crizotinib (crizo) in patients with metastatic castration resistant prostate cancer (CRPC)</article-title><source>Ann. Oncol.</source><year>2018</year><volume>29</volume><pub-id pub-id-type="doi">10.1093/annonc/mdy284.061</pub-id></element-citation></ref><ref id="B154-cells-08-01013"><label>154.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kato</surname><given-names>S.</given-names></name><name><surname>Jardim</surname><given-names>D.L.</given-names></name><name><surname>Johnson</surname><given-names>F.M.</given-names></name><name><surname>Subbiah</surname><given-names>V.</given-names></name><name><surname>Piha-Paul</surname><given-names>S.</given-names></name><name><surname>Tsimberidou</surname><given-names>A.M.</given-names></name><name><surname>Falchook</surname><given-names>G.S.</given-names></name><name><surname>Karp</surname><given-names>D.</given-names></name><name><surname>Zinner</surname><given-names>R.</given-names></name><name><surname>Wheler</surname><given-names>J.</given-names></name><etal></etal></person-group><article-title>Phase I study of the combination of crizotinib (as a MET inhibitor) and dasatinib (as a c-SRC inhibitor) in patients with advanced cancer</article-title><source>Invest. New Drugs</source><year>2018</year><volume>36</volume><fpage>416</fpage><lpage>423</lpage><pub-id pub-id-type="doi">10.1007/s10637-017-0513-5</pub-id><pub-id pub-id-type="pmid">29047029</pub-id></element-citation></ref><ref id="B155-cells-08-01013"><label>155.</label><element-citation publication-type="gov"><article-title>Dasatinib and Crizotinib in Advanced Cancer - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01744652?term=crizotinib&recrs=de&rank=6">https://clinicaltrials.gov/ct2/show/NCT01744652?term=crizotinib&recrs=de&rank=6</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B156-cells-08-01013"><label>156.</label><element-citation publication-type="gov"><article-title>Study of the Combination of Crizotinib and Dasatinib in Pediatric Research Participants With Diffuse Pontine Glioma (DIPG) and High-Grade Glioma (HGG) - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01644773?term=crizotinib&recrs=de&rank=22">https://clinicaltrials.gov/ct2/show/NCT01644773?term=crizotinib&recrs=de&rank=22</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B157-cells-08-01013"><label>157.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Michmerhuizen</surname><given-names>N.L.</given-names></name><name><surname>Leonard</surname><given-names>E.</given-names></name><name><surname>Matovina</surname><given-names>C.</given-names></name><name><surname>Harris</surname><given-names>M.</given-names></name><name><surname>Herbst</surname><given-names>G.</given-names></name><name><surname>Kulkarni</surname><given-names>A.</given-names></name><name><surname>Zhai</surname><given-names>J.</given-names></name><name><surname>Jiang</surname><given-names>H.</given-names></name><name><surname>Carey</surname><given-names>T.E.</given-names></name><name><surname>Brenner</surname><given-names>J.C.</given-names></name></person-group><article-title>Rationale for Using Irreversible Epidermal Growth Factor Receptor Inhibitors in Combination with Phosphatidylinositol 3-Kinase Inhibitors for Advanced Head and Neck Squamous Cell Carcinoma</article-title><source>Mol. Pharmacol.</source><year>2019</year><volume>95</volume><fpage>528</fpage><lpage>536</lpage><pub-id pub-id-type="doi">10.1124/mol.118.115162</pub-id><pub-id pub-id-type="pmid">30858165</pub-id></element-citation></ref><ref id="B158-cells-08-01013"><label>158.</label><element-citation publication-type="gov"><article-title>Copanlisib in Association With Cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinomas Harboring a PI3KCA Mutation/Amplification and/or a PTEN Loss - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02822482?term=copanlisib&rank=2">https://clinicaltrials.gov/ct2/show/NCT02822482?term=copanlisib&rank=2</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B159-cells-08-01013"><label>159.</label><element-citation publication-type="gov"><article-title>Pazopanib and Everolimus in PI3KCA Mutation Positive/PTEN Loss Patients - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01430572">https://clinicaltrials.gov/ct2/show/NCT01430572</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B160-cells-08-01013"><label>160.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Barr</surname><given-names>P.M.</given-names></name><name><surname>Saylors</surname><given-names>G.B.</given-names></name><name><surname>Spurgeon</surname><given-names>S.E.</given-names></name><name><surname>Cheson</surname><given-names>B.D.</given-names></name><name><surname>Greenwald</surname><given-names>D.R.</given-names></name><name><surname>OBrien</surname><given-names>S.M.</given-names></name><name><surname>Liem</surname><given-names>A.K.D.</given-names></name><name><surname>Mclntyre</surname><given-names>R.E.</given-names></name><name><surname>Joshi</surname><given-names>A.</given-names></name><name><surname>Abella-Dominicis</surname><given-names>E.</given-names></name><etal></etal></person-group><article-title>Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL</article-title><source>Blood</source><year>2016</year><volume>127</volume><fpage>2411</fpage><lpage>2415</lpage><pub-id pub-id-type="doi">10.1182/blood-2015-12-683516</pub-id><pub-id pub-id-type="pmid">26968534</pub-id></element-citation></ref><ref id="B161-cells-08-01013"><label>161.</label><element-citation publication-type="gov"><article-title>A Study of Abemaciclib (LY2835219) Alone or in Combination With Other Agents in Participants With Previously Treated Pancreatic Ductal Adenocarcinoma - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02981342?term=NCT02981342&rank=1">https://clinicaltrials.gov/ct2/show/NCT02981342?term=NCT02981342&rank=1</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B162-cells-08-01013"><label>162.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Keam</surname><given-names>B.</given-names></name><name><surname>Tahara</surname><given-names>M.</given-names></name><name><surname>Lin</surname><given-names>J.-C.</given-names></name><name><surname>Sacco</surname><given-names>A.G.</given-names></name><name><surname>Melichar</surname><given-names>B.</given-names></name><name><surname>Baney</surname><given-names>T.</given-names></name><name><surname>Hoffman</surname><given-names>J.</given-names></name><name><surname>Wang</surname><given-names>D.D.</given-names></name><name><surname>Wang</surname><given-names>S.L.</given-names></name><name><surname>Martini</surname><given-names>J.-F.</given-names></name><etal></etal></person-group><article-title>An international, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2 study of palbociclib (an oral CDK4/6 inhibitor) plus cetuximab in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN)</article-title><source>J. Clin. Oncol.</source><year>2016</year><volume>34</volume><fpage>TPS6102</fpage></element-citation></ref><ref id="B163-cells-08-01013"><label>163.</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Sullivan</surname><given-names>R.J.</given-names></name><name><surname>Amaria</surname><given-names>R.N.</given-names></name><name><surname>Lawrence</surname><given-names>D.P.</given-names></name><name><surname>Brennan</surname><given-names>J.</given-names></name><name><surname>Leister</surname><given-names>C.</given-names></name><name><surname>Singh</surname><given-names>R.</given-names></name><name><surname>Legos</surname><given-names>J.</given-names></name><name><surname>Thurm</surname><given-names>H.</given-names></name><name><surname>Yan</surname><given-names>L.</given-names></name><name><surname>Flaherty</surname><given-names>K.T.</given-names></name><etal></etal></person-group><article-title>Abstract PR06: Phase 1b dose-escalation study of trametinib (MEKi) plus palbociclib (CDK4/6i) in patients with advanced solid tumors</article-title><source>Proceedings of the MAPK Pathways</source><publisher-name>American Association for Cancer Research</publisher-name><publisher-loc>Philadelphia, PA, USA</publisher-loc><year>2015</year><fpage>PR06</fpage></element-citation></ref><ref id="B164-cells-08-01013"><label>164.</label><element-citation publication-type="gov"><article-title>A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Anti-Cancer Activity of Trametinib in Combination With Palbociclib in Subjects With Solid Tumors - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02065063">https://clinicaltrials.gov/ct2/show/NCT02065063</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-15">(accessed on 15 July 2019)</date-in-citation></element-citation></ref><ref id="B165-cells-08-01013"><label>165.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berghoff</surname><given-names>A.S.</given-names></name><name><surname>Preusser</surname><given-names>M.</given-names></name></person-group><article-title>Targeted Therapies for Melanoma Brain Metastases</article-title><source>Curr. Treat. Options Neurol.</source><year>2017</year><volume>19</volume><fpage>13</fpage><pub-id pub-id-type="doi">10.1007/s11940-017-0449-2</pub-id><pub-id pub-id-type="pmid">28374234</pub-id></element-citation></ref><ref id="B166-cells-08-01013"><label>166.</label><element-citation publication-type="gov"><article-title>Vemurafenib and Cobimetinib Combination in BRAF Mutated Melanoma With Brain Metastasis - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02537600?term=vemurafenib&rank=7">https://clinicaltrials.gov/ct2/show/NCT02537600?term=vemurafenib&rank=7</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B167-cells-08-01013"><label>167.</label><element-citation publication-type="gov"><article-title>A Study of Tarceva (Erlotinib) and Avastin (Bevacizumab) in Patients With Advanced or Metastatic Liver Cancer. - Full Text View - ClinicalTrials.gov</article-title><comment>Available online: <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT00605722?term=00605722&rank=1">https://clinicaltrials.gov/ct2/show/NCT00605722?term=00605722&rank=1</ext-link></comment><date-in-citation content-type="access-date" iso-8601-date="2019-07-14">(accessed on 14 July 2019)</date-in-citation></element-citation></ref><ref id="B168-cells-08-01013"><label>168.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nissan</surname><given-names>M.H.</given-names></name><name><surname>Rosen</surname><given-names>N.</given-names></name><name><surname>Solit</surname><given-names>D.B.</given-names></name></person-group><article-title>ERK Pathway Inhibitors: How Low Should We Go?</article-title><source>Cancer Discov.</source><year>2013</year><volume>3</volume><fpage>719</fpage><lpage>721</lpage><pub-id pub-id-type="doi">10.1158/2159-8290.CD-13-0245</pub-id><pub-id pub-id-type="pmid">23847348</pub-id></element-citation></ref><ref id="B169-cells-08-01013"><label>169.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Flaherty</surname><given-names>K.T.</given-names></name><name><surname>Infante</surname><given-names>J.R.</given-names></name><name><surname>Daud</surname><given-names>A.</given-names></name><name><surname>Gonzalez</surname><given-names>R.</given-names></name><name><surname>Kefford</surname><given-names>R.F.</given-names></name><name><surname>Sosman</surname><given-names>J.</given-names></name><name><surname>Hamid</surname><given-names>O.</given-names></name><name><surname>Schuchter</surname><given-names>L.</given-names></name><name><surname>Cebon</surname><given-names>J.</given-names></name><name><surname>Ibrahim</surname><given-names>N.</given-names></name><etal></etal></person-group><article-title>Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations</article-title><source>N. Engl. J. Med.</source><year>2012</year><volume>367</volume><fpage>1694</fpage><lpage>1703</lpage><pub-id pub-id-type="doi">10.1056/NEJMoa1210093</pub-id><pub-id pub-id-type="pmid">23020132</pub-id></element-citation></ref><ref id="B170-cells-08-01013"><label>170.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pelster</surname><given-names>M.S.</given-names></name><name><surname>Amaria</surname><given-names>R.N.</given-names></name></person-group><article-title>Combined targeted therapy and immunotherapy in melanoma: a review of the impact on the tumor microenvironment and outcomes of early clinical trials</article-title><source>Ther. Adv. Med. Oncol.</source><year>2019</year><pub-id pub-id-type="doi">10.1177/1758835919830826</pub-id><pub-id pub-id-type="pmid">30815041</pub-id></element-citation></ref><ref id="B171-cells-08-01013"><label>171.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jaiswal</surname><given-names>B.S.</given-names></name><name><surname>Durinck</surname><given-names>S.</given-names></name><name><surname>Stawiski</surname><given-names>E.W.</given-names></name><name><surname>Yin</surname><given-names>J.</given-names></name><name><surname>Wang</surname><given-names>W.</given-names></name><name><surname>Lin</surname><given-names>E.</given-names></name><name><surname>Moffat</surname><given-names>J.</given-names></name><name><surname>Martin</surname><given-names>S.E.</given-names></name><name><surname>Modrusan</surname><given-names>Z.</given-names></name><name><surname>Seshagiri</surname><given-names>S.</given-names></name></person-group><article-title>ERK Mutations and amplification confer resistance to ERK-inhibitor therapy</article-title><source>Clin. Cancer Res.</source><year>2018</year><volume>24</volume><fpage>4044</fpage><lpage>4055</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.CCR-17-3674</pub-id><pub-id pub-id-type="pmid">29760222</pub-id></element-citation></ref><ref id="B172-cells-08-01013"><label>172.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sullivan</surname><given-names>R.J.</given-names></name><name><surname>Infante</surname><given-names>J.R.</given-names></name><name><surname>Janku</surname><given-names>F.</given-names></name><name><surname>Lee Wong</surname><given-names>D.J.</given-names></name><name><surname>Sosman</surname><given-names>J.A.</given-names></name><name><surname>Keedy</surname><given-names>V.</given-names></name><name><surname>Patel</surname><given-names>M.R.</given-names></name><name><surname>Shapiro</surname><given-names>G.I.</given-names></name><name><surname>Mier</surname><given-names>J.W.</given-names></name><name><surname>Tolcher</surname><given-names>A.W.</given-names></name><etal></etal></person-group><article-title>First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: Results of a phase I dose-escalation and expansion study</article-title><source>Cancer Discov.</source><year>2018</year><volume>8</volume><fpage>184</fpage><lpage>192</lpage><pub-id pub-id-type="doi">10.1158/2159-8290.CD-17-1119</pub-id><pub-id pub-id-type="pmid">29247021</pub-id></element-citation></ref><ref id="B173-cells-08-01013"><label>173.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Janku</surname><given-names>F.</given-names></name><name><surname>Yap</surname><given-names>T.A.</given-names></name><name><surname>Meric-Bernstam</surname><given-names>F.</given-names></name></person-group><article-title>Targeting the PI3K pathway in cancer: Are we making headway?</article-title><source>Nat. Rev. Clin. Oncol.</source><year>2018</year><volume>15</volume><fpage>273</fpage><lpage>291</lpage><pub-id pub-id-type="doi">10.1038/nrclinonc.2018.28</pub-id><pub-id pub-id-type="pmid">29508857</pub-id></element-citation></ref><ref id="B174-cells-08-01013"><label>174.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hanker</surname><given-names>A.B.</given-names></name><name><surname>Kaklamani</surname><given-names>V.</given-names></name><name><surname>Arteaga</surname><given-names>C.L.</given-names></name></person-group><article-title>Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors</article-title><source>Cancer Discov.</source><year>2019</year><volume>9</volume><pub-id pub-id-type="doi">10.1158/2159-8290.CD-18-1175</pub-id></element-citation></ref><ref id="B175-cells-08-01013"><label>175.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Curigliano</surname><given-names>G.</given-names></name><name><surname>Shah</surname><given-names>R.R.</given-names></name></person-group><article-title>Safety and Tolerability of Phosphatidylinositol-3-Kinase (PI3K) Inhibitors in Oncology</article-title><source>Drug Saf.</source><year>2019</year><volume>42</volume><fpage>247</fpage><lpage>262</lpage><pub-id pub-id-type="doi">10.1007/s40264-018-0778-4</pub-id><pub-id pub-id-type="pmid">30649751</pub-id></element-citation></ref><ref id="B176-cells-08-01013"><label>176.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Song</surname><given-names>M.</given-names></name><name><surname>Bode</surname><given-names>A.M.</given-names></name><name><surname>Dong</surname><given-names>Z.</given-names></name><name><surname>Lee</surname><given-names>M.H.</given-names></name></person-group><article-title>AKt as a therapeutic target for cancer</article-title><source>Cancer Res.</source><year>2019</year><pub-id pub-id-type="doi">10.1158/0008-5472.CAN-18-2738</pub-id><pub-id pub-id-type="pmid">30808672</pub-id></element-citation></ref><ref id="B177-cells-08-01013"><label>177.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sampath</surname><given-names>D.</given-names></name><name><surname>Malik</surname><given-names>A.</given-names></name><name><surname>Plunkett</surname><given-names>W.</given-names></name><name><surname>Nowak</surname><given-names>B.</given-names></name><name><surname>Williams</surname><given-names>B.</given-names></name><name><surname>Burton</surname><given-names>M.</given-names></name><name><surname>Verstovsek</surname><given-names>S.</given-names></name><name><surname>Faderl</surname><given-names>S.</given-names></name><name><surname>Garcia-Manero</surname><given-names>G.</given-names></name><name><surname>List</surname><given-names>A.F.</given-names></name><etal></etal></person-group><article-title>Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies</article-title><source>Leuk. Res.</source><year>2013</year><volume>37</volume><fpage>1461</fpage><lpage>1467</lpage><pub-id pub-id-type="doi">10.1016/j.leukres.2013.07.034</pub-id><pub-id pub-id-type="pmid">23993427</pub-id></element-citation></ref><ref id="B178-cells-08-01013"><label>178.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sunyoto</surname><given-names>T.</given-names></name><name><surname>Potet</surname><given-names>J.</given-names></name><name><surname>Boelaert</surname><given-names>M.</given-names></name></person-group><article-title>Why miltefosine - A life-saving drug for leishmaniasis-is unavailable to people who need it the most</article-title><source>BMJ Glob. Heal.</source><year>2018</year><pub-id pub-id-type="doi">10.1136/bmjgh-2018-000709</pub-id><pub-id pub-id-type="pmid">29736277</pub-id></element-citation></ref><ref id="B179-cells-08-01013"><label>179.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ghidini</surname><given-names>M.</given-names></name><name><surname>Petrelli</surname><given-names>F.</given-names></name><name><surname>Ghidini</surname><given-names>A.</given-names></name><name><surname>Tomasello</surname><given-names>G.</given-names></name><name><surname>Hahne</surname><given-names>J.C.</given-names></name><name><surname>Passalacqua</surname><given-names>R.</given-names></name><name><surname>Barni</surname><given-names>S.</given-names></name></person-group><article-title>Clinical development of mTor inhibitors for renal cancer</article-title><source>Expert Opin. Investig. Drugs</source><year>2017</year><volume>26</volume><fpage>1229</fpage><lpage>1237</lpage><pub-id pub-id-type="doi">10.1080/13543784.2017.1384813</pub-id><pub-id pub-id-type="pmid">28952411</pub-id></element-citation></ref><ref id="B180-cells-08-01013"><label>180.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Teng</surname><given-names>Q.-X.</given-names></name><name><surname>Ashar</surname><given-names>Y.V.</given-names></name><name><surname>Gupta</surname><given-names>P.</given-names></name><name><surname>Gadee</surname><given-names>E.</given-names></name><name><surname>Fan</surname><given-names>Y.-F.</given-names></name><name><surname>Reznik</surname><given-names>S.E.</given-names></name><name><surname>Wurpel</surname><given-names>J.N.D.</given-names></name><name><surname>Chen</surname><given-names>Z.-S.</given-names></name></person-group><article-title>Revisiting mTOR inhibitors as anticancer agents</article-title><source>Drug Discov. Today</source><year>2019</year><pub-id pub-id-type="doi">10.1016/j.drudis.2019.05.030</pub-id></element-citation></ref><ref id="B181-cells-08-01013"><label>181.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Prasad</surname><given-names>V.</given-names></name><name><surname>De Jesús</surname><given-names>K.</given-names></name><name><surname>Mailankody</surname><given-names>S.</given-names></name></person-group><article-title>The high price of anticancer drugs: origins, implications, barriers, solutions</article-title><source>Nat. Rev. Clin. Oncol.</source><year>2017</year><volume>14</volume><fpage>381</fpage><lpage>390</lpage><pub-id pub-id-type="doi">10.1038/nrclinonc.2017.31</pub-id><pub-id pub-id-type="pmid">28290490</pub-id></element-citation></ref><ref id="B182-cells-08-01013"><label>182.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Turk</surname><given-names>A.A.</given-names></name><name><surname>Wisinski</surname><given-names>K.B.</given-names></name></person-group><article-title>PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside</article-title><source>Cancer</source><year>2018</year><volume>124</volume><fpage>2498</fpage><lpage>2506</lpage><pub-id pub-id-type="doi">10.1002/cncr.31307</pub-id><pub-id pub-id-type="pmid">29660759</pub-id></element-citation></ref><ref id="B183-cells-08-01013"><label>183.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Helleday</surname><given-names>T.</given-names></name></person-group><article-title>The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings</article-title><source>Mol. Oncol.</source><year>2011</year><volume>5</volume><fpage>387</fpage><lpage>393</lpage><pub-id pub-id-type="doi">10.1016/j.molonc.2011.07.001</pub-id><pub-id pub-id-type="pmid">21821475</pub-id></element-citation></ref><ref id="B184-cells-08-01013"><label>184.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Heinzel</surname><given-names>A.</given-names></name><name><surname>Marhold</surname><given-names>M.</given-names></name><name><surname>Mayer</surname><given-names>P.</given-names></name><name><surname>Schwarz</surname><given-names>M.</given-names></name><name><surname>Tomasich</surname><given-names>E.</given-names></name><name><surname>Lukas</surname><given-names>A.</given-names></name><name><surname>Krainer</surname><given-names>M.</given-names></name><name><surname>Perco</surname><given-names>P.</given-names></name></person-group><article-title>Synthetic lethality guiding selection of drug combinations in ovarian cancer</article-title><source>PLoS ONE</source><year>2019</year><volume>14</volume><elocation-id>e0210859</elocation-id><pub-id pub-id-type="doi">10.1371/journal.pone.0210859</pub-id><pub-id pub-id-type="pmid">30682083</pub-id></element-citation></ref><ref id="B185-cells-08-01013"><label>185.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gupta</surname><given-names>S.C.</given-names></name><name><surname>Sung</surname><given-names>B.</given-names></name><name><surname>Prasad</surname><given-names>S.</given-names></name><name><surname>Webb</surname><given-names>L.J.</given-names></name><name><surname>Aggarwal</surname><given-names>B.B.</given-names></name></person-group><article-title>Cancer drug discovery by repurposing: Teaching new tricks to old dogs</article-title><source>Trends Pharmacol. Sci.</source><year>2013</year><pub-id pub-id-type="doi">10.1016/j.tips.2013.06.005</pub-id></element-citation></ref><ref id="B186-cells-08-01013"><label>186.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bertolini</surname><given-names>F.</given-names></name><name><surname>Sukhatme</surname><given-names>V.P.</given-names></name><name><surname>Bouche</surname><given-names>G.</given-names></name></person-group><article-title>Drug repurposing in oncology-patient and health systems opportunities</article-title><source>Nat. Rev. Clin. Oncol.</source><year>2015</year><pub-id pub-id-type="doi">10.1038/nrclinonc.2015.169</pub-id><pub-id pub-id-type="pmid">26483297</pub-id></element-citation></ref><ref id="B187-cells-08-01013"><label>187.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>X.</given-names></name><name><surname>Shen</surname><given-names>C.</given-names></name><name><surname>Liu</surname><given-names>Z.</given-names></name><name><surname>Peng</surname><given-names>F.</given-names></name><name><surname>Chen</surname><given-names>X.</given-names></name><name><surname>Yang</surname><given-names>G.</given-names></name><name><surname>Zhang</surname><given-names>D.</given-names></name><name><surname>Yin</surname><given-names>Z.</given-names></name><name><surname>Ma</surname><given-names>J.</given-names></name><name><surname>Zheng</surname><given-names>Z.</given-names></name><etal></etal></person-group><article-title>Nitazoxanide, an antiprotozoal drug, inhibits late-stage autophagy and promotes ING1-induced cell cycle arrest in glioblastoma</article-title><source>Cell Death Dis.</source><year>2018</year><volume>9</volume><fpage>1032</fpage><pub-id pub-id-type="doi">10.1038/s41419-018-1058-z</pub-id><pub-id pub-id-type="pmid">30302016</pub-id></element-citation></ref><ref id="B188-cells-08-01013"><label>188.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hendouei</surname><given-names>N.</given-names></name><name><surname>Saghafi</surname><given-names>F.</given-names></name><name><surname>Shadfar</surname><given-names>F.</given-names></name><name><surname>Hosseinimehr</surname><given-names>S.J.</given-names></name></person-group><article-title>Molecular mechanisms of anti-psychotic drugs for improvement of cancer treatment</article-title><source>Eur. J. Pharmacol.</source><year>2019</year><volume>856</volume><fpage>172402</fpage><pub-id pub-id-type="doi">10.1016/j.ejphar.2019.05.031</pub-id><pub-id pub-id-type="pmid">31108054</pub-id></element-citation></ref><ref id="B189-cells-08-01013"><label>189.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>W.-Y.</given-names></name><name><surname>Lee</surname><given-names>W.-T.</given-names></name><name><surname>Cheng</surname><given-names>C.-H.</given-names></name><name><surname>Chen</surname><given-names>K.-C.</given-names></name><name><surname>Chou</surname><given-names>C.-M.</given-names></name><name><surname>Chung</surname><given-names>C.-H.</given-names></name><name><surname>Sun</surname><given-names>M.-S.</given-names></name><name><surname>Cheng</surname><given-names>H.-W.</given-names></name><name><surname>Ho</surname><given-names>M.-N.</given-names></name><name><surname>Lin</surname><given-names>C.-W.</given-names></name></person-group><article-title>Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1</article-title><source>Oncotarget</source><year>2015</year><volume>6</volume><fpage>27580</fpage><lpage>27595</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.4768</pub-id><pub-id pub-id-type="pmid">26363315</pub-id></element-citation></ref><ref id="B190-cells-08-01013"><label>190.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Soletti</surname><given-names>R.C.</given-names></name><name><surname>Biasoli</surname><given-names>D.</given-names></name><name><surname>Rodrigues</surname><given-names>N.A.L.V.</given-names></name><name><surname>Delou</surname><given-names>J.M.A.</given-names></name><name><surname>Maciel</surname><given-names>R.</given-names></name><name><surname>Chagas</surname><given-names>V.L.A.</given-names></name><name><surname>Martins</surname><given-names>R.A.P.</given-names></name><name><surname>Rehen</surname><given-names>S.K.</given-names></name><name><surname>Borges</surname><given-names>H.L.</given-names></name></person-group><article-title>Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells</article-title><source>Transl. Oncol.</source><year>2017</year><volume>10</volume><fpage>726</fpage><lpage>733</lpage><pub-id pub-id-type="doi">10.1016/j.tranon.2017.06.008</pub-id><pub-id pub-id-type="pmid">28734226</pub-id></element-citation></ref><ref id="B191-cells-08-01013"><label>191.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Laurent</surname><given-names>M.</given-names></name><name><surname>Brahmi</surname><given-names>M.</given-names></name><name><surname>Dufresne</surname><given-names>A.</given-names></name><name><surname>Meeus</surname><given-names>P.</given-names></name><name><surname>Karanian</surname><given-names>M.</given-names></name><name><surname>Ray-Coquard</surname><given-names>I.</given-names></name><name><surname>Blay</surname><given-names>J.-Y.</given-names></name></person-group><article-title>Adjuvant therapy with imatinib in gastrointestinal stromal tumors (GISTs)—review and perspectives</article-title><source>Transl. Gastroenterol. Hepatol.</source><year>2019</year><volume>4</volume><fpage>24</fpage><pub-id pub-id-type="doi">10.21037/tgh.2019.03.07</pub-id><pub-id pub-id-type="pmid">31143845</pub-id></element-citation></ref><ref id="B192-cells-08-01013"><label>192.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brown</surname><given-names>A.S.</given-names></name><name><surname>Patel</surname><given-names>C.J.</given-names></name></person-group><article-title>A standard database for drug repositioning</article-title><source>Sci. Data</source><year>2017</year><volume>4</volume><fpage>170029</fpage><pub-id pub-id-type="doi">10.1038/sdata.2017.29</pub-id><pub-id pub-id-type="pmid">28291243</pub-id></element-citation></ref><ref id="B193-cells-08-01013"><label>193.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Aberle</surname><given-names>M.R.</given-names></name><name><surname>Burkhart</surname><given-names>R.A.</given-names></name><name><surname>Tiriac</surname><given-names>H.</given-names></name><name><surname>Olde Damink</surname><given-names>S.W.M.</given-names></name><name><surname>Dejong</surname><given-names>C.H.C.</given-names></name><name><surname>Tuveson</surname><given-names>D.A.</given-names></name><name><surname>van Dam</surname><given-names>R.M.</given-names></name></person-group><article-title>Patient-derived organoid models help define personalized management of gastrointestinal cancer</article-title><source>Br. J. Surg.</source><year>2018</year><volume>105</volume><fpage>e48</fpage><lpage>e60</lpage><pub-id pub-id-type="doi">10.1002/bjs.10726</pub-id><pub-id pub-id-type="pmid">29341164</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="cells-08-01013-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Targets of approved or investigational pharmacological intervention on signaling pathways associated with resistance mechanisms against antineoplastic agents and their associations with the hallmarks of cancer. The hallmarks of cancer [<xref rid="B91-cells-08-01013" ref-type="bibr">91</xref>] are sustaining proliferative signaling, evasion of growth suppression, avoiding immune destruction, enabling replicative immortality, tumor-promoting inflammation, activation invasion and metastasis, inducing angiogenesis, genome instability and mutation, resisting cell death, and deregulating cellular energetics. The most commonly affected signaling pathways in response to cytotoxic or targeted chemotherapeutic agents related to specific resistance mechanisms are depicted. For more details, please consult the <xref ref-type="app" rid="app1-cells-08-01013">supplementary tables</xref>. Adapted from Hanahan and Weinberg (2011) [<xref rid="B91-cells-08-01013" ref-type="bibr">91</xref>].</p></caption><graphic xlink:href="cells-08-01013-g001"></graphic></fig><table-wrap id="cells-08-01013-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-01013-t001_Table 1</object-id><label>Table 1</label><caption><p>Most common specific resistance mechanisms and signaling pathways associated with cytotoxic and targeted therapies.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" rowspan="1" colspan="1">Top</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cytotoxic Drugs (<italic>N</italic> = 59)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Drugs Affected</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" rowspan="1" colspan="1">%</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Targeted Drugs (<italic>N</italic> = 117)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Drugs Affected</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">%</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">1</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">ABC transporters</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">21</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">36</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">MAPK family</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">34</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">29</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">2</td><td align="left" valign="middle" rowspan="1" colspan="1">Enzymatic detoxification</td><td align="center" valign="middle" rowspan="1" colspan="1">9</td><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">17</td><td align="left" valign="middle" rowspan="1" colspan="1">PI3K-AKT-mTOR</td><td align="center" valign="middle" rowspan="1" colspan="1">33</td><td align="center" valign="middle" rowspan="1" colspan="1">28</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">3</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Mutation in and/or downregulation of topoisomerases I/II</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">7</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">12</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">EGF and EGFR</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">21</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">18</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">4</td><td align="left" valign="middle" rowspan="1" colspan="1">Mutation in and/or overexpression of tubulins</td><td align="center" valign="middle" rowspan="1" colspan="1">6</td><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">10</td><td align="left" valign="middle" rowspan="1" colspan="1">PTEN</td><td align="center" valign="middle" rowspan="1" colspan="1">14</td><td align="center" valign="middle" rowspan="1" colspan="1">12</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">5</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Decreased dCK</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">6</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">8</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">ABC transporters</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">14</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">12</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">6</td><td align="left" valign="middle" rowspan="1" colspan="1">Increased activity of GST</td><td align="center" valign="middle" rowspan="1" colspan="1">5</td><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">8</td><td align="left" valign="middle" rowspan="1" colspan="1">IGFs</td><td align="center" valign="middle" rowspan="1" colspan="1">14</td><td align="center" valign="middle" rowspan="1" colspan="1">12</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">7</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Activation of NF-κB</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">7</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">JAK/STAT</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">14</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">12</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">8</td><td align="left" valign="middle" rowspan="1" colspan="1">Increased MGMT</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">7</td><td align="left" valign="middle" rowspan="1" colspan="1">BCL-2 family</td><td align="center" valign="middle" rowspan="1" colspan="1">13</td><td align="center" valign="middle" rowspan="1" colspan="1">12</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">9</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Increased levels of ALDH1</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">3</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">5</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">FGFs</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">12</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">11</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin;border-right:solid thin" rowspan="1" colspan="1">10</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Silencing or mutations in TP53</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3</td><td align="center" valign="middle" style="border-bottom:solid thin;border-right:solid thin" rowspan="1" colspan="1">5</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ERBB2 (HER2)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11</td></tr></tbody></table><table-wrap-foot><fn><p>N = FDA approved antineoplastic drugs available as at May 2019. Abbreviations: ABC—ATP-binding cassette, dCK—deoxycytidine kinase, GST—glutathione s-transferase, NF-κB—factor nuclear kappa B, MGMT—O-6-methylguanine-DNA methyltransferase, ALDH1—aldehyde dehydrogenase 1 family, TP53—tumor protein p53, MAPK—mitogen activated protein kinases, PI3K—phosphoinositide 3-kinase, AKT—protein kinase B, mTOR—mammalian target of rapamycin, EGF—epithelial growth factor, EGFR—epithelial growth factor receptor, PTEN—phosphatase and tensin homolog, IGF—insulin-like growth factor 1, JAK—Janus kinase, STAT—signal transducer and activator of transcription, BCL2—B-cell lymphoma 2, FGF—fibroblast growth factor, ERBB2—erb-b2 receptor tyrosine kinase 2, HER2—human epidermal growth factor receptor 2.</p></fn></table-wrap-foot></table-wrap><table-wrap id="cells-08-01013-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-01013-t002_Table 2</object-id><label>Table 2</label><caption><p>Hallmarks of cancer and signaling pathways associated with specific resistance mechanisms.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Top</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cytotoxic (<italic>N</italic> = 59)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Drugs Affected</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" rowspan="1" colspan="1">%</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Targeted therapies (<italic>N</italic> = 117)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Drugs Affected</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">%</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1"><bold>1</bold></td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>Metabolism</bold><break></break> (Detoxification transporters and enzymes, protection from ROS, increased glucose metabolism)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">21</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">36</td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>Sustaining Proliferative Signaling</bold><break></break> (GF, Hedgehog, MAPK, PI3K, WNT, autophagy induction)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">65</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">56</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1"><bold>2</bold></td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Sustaining Proliferative Signaling</bold><break></break> (GF, Hedgehog, MAPK, PI3K, WNT, autophagy induction)</td><td align="center" valign="middle" rowspan="1" colspan="1">19</td><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">32</td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Cell Death Evasion</bold><break></break> (BCL2 family, TP53, MDM2, PTEN, NF-KB, autophagy induction)</td><td align="center" valign="middle" rowspan="1" colspan="1">41</td><td align="center" valign="middle" rowspan="1" colspan="1">35</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1"><bold>3</bold></td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>Cell Death Evasion</bold><break></break> (BCL2 family, TP53, MDM2, PTEN, NF-KB, autophagy induction)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">10</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">17</td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>Angiogenesis</bold><break></break> (EGF, IGF, FGF, VEGF, PDGF)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">31</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">26</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1"><bold>4</bold></td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Genome instability</bold><break></break> (TP53, MDM2, NHEJ, RAD51, CHEK1/2, BRCA1/2, HDAC)</td><td align="center" valign="middle" rowspan="1" colspan="1">5</td><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">8</td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Metabolism</bold><break></break> (Detoxification transporters and enzymes, protection from ROS, increased glucose metabolism)</td><td align="center" valign="middle" rowspan="1" colspan="1">21</td><td align="center" valign="middle" rowspan="1" colspan="1">18</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1"><bold>5</bold></td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>Evading growth suppressors</bold><break></break> (TP53, RB, cyclins, CDKs, p16, p18, p21)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">7</td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>Genome instability</bold><break></break> (TP53, MDM2, NHEJ, RAD51, CHEK1/2, BRCA1/2, HDAC, p21)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">18</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">15</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1"><bold>6</bold></td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Inflammation</bold><break></break> (NF-kB)</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">7</td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Immune checkpoint</bold><break></break> (CD19, CD20, CTLA-4, NT5E, PCLP, PD-1, PD-L1)</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">14</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1"><bold>7</bold></td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>Angiogenesis</bold><break></break> (EGF, IGF, FGF, VEGF, PDGF)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">2</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">3</td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>Evading growth suppressors</bold><break></break> (TP53, RB, cyclins, CDKs, p16, p18, p21)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">13</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">11</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1"><bold>8</bold></td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Immune checkpoint</bold><break></break> (CD19, CD20, CTLA-4, NT5E, PCLP, PD-1, PD-L1)</td><td align="center" valign="middle" rowspan="1" colspan="1">0</td><td align="center" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1">0</td><td align="left" valign="top" rowspan="1" colspan="1"><bold>EMT, invasion, and metastasis</bold><break></break> (EMT phenotype, integrin)</td><td align="center" valign="middle" rowspan="1" colspan="1">13</td><td align="center" valign="middle" rowspan="1" colspan="1">11</td></tr><tr><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1"><bold>9</bold></td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>EMT, invasion, and metastasis</bold><break></break> (EMT phenotype, integrin)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">0</td><td align="center" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1">0</td><td align="left" valign="top" style="background:#F2F2F2" rowspan="1" colspan="1"><bold>Inflammation</bold><break></break> (NF-kB)</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">12</td><td align="center" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">10</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin;border-right:solid thin" rowspan="1" colspan="1"><bold>10</bold></td><td align="left" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Replicative immortality</bold><break></break> (WNT, Hedgehog, TERT)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0</td><td align="center" valign="middle" style="border-bottom:solid thin;border-right:solid thin" rowspan="1" colspan="1">0</td><td align="left" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Replicative immortality</bold><break></break> (WNT, Hedgehog, TERT)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">7</td></tr></tbody></table><table-wrap-foot><fn><p>N = FDA approved antineoplastic drugs available as at May 2019. Abbreviations: NF-κB—factor nuclear kappa B, TP53—tumor protein p53, MAPK—mitogen activated protein kinases, PI3K—phosphoinositide 3-kinase, EGF—epithelial growth factor, PTEN—phosphatase and tensin homolog, IGF—insulin-like growth factor 1, JAK—Janus kinase, STAT—signal transducer and activator of transcription, BCL2—B-cell lymphoma 2, FGF—fibroblast growth factor, ERBB2—erb-b2 receptor tyrosine kinase 2, HER2—human epidermal growth factor receptor 2, ROS—reactive oxygen species, GF—growth factor, NHEJ—non-homologous end joining, RAD51—RAD51 recombinase, CHEK1/2—checkpoint kinases 1 and 2, BRCA1/2—breast cancer type 1 susceptibility protein, and 2, HDAC—histone deacetylase, RB—retinoblastoma protein, CDKs—cyclin-dependent kinase, PDGF—platelet-derived growth factor, CTLA-4—cytotoxic T lymphocyte antigen 4, NT5E—ecto-5′-nucleotidase, PCLP—podocalyxin-like protein 1, PD-1—programmed cell death protein 1, PD-L1—programmed death-ligand 1, EMT—epithelial–mesenchymal transition, TERT—telomerase reverse transcriptase.</p></fn></table-wrap-foot></table-wrap><table-wrap id="cells-08-01013-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-01013-t003_Table 3</object-id><label>Table 3</label><caption><p>Clinical trials with combinations in which targeted therapies inhibit resistance mechanisms of cytotoxic drugs.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Signalling Pathway Affected</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Targeted Drug/Inhibitor Drug</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cytotoxic Drugs</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Clinical Trial Phase</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Indications</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Obs</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">References</th></tr></thead><tbody><tr><td rowspan="2" align="left" valign="middle" style="border-right:solid thin;background:#F2F2F2" colspan="1"><bold>BCR-ABL</bold></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Bosutinib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Pemetrexed</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Bladder, cervical, NSCLC, ovarian</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Recruiting</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B109-cells-08-01013" ref-type="bibr">109</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Dasatinib</td><td align="left" valign="middle" rowspan="1" colspan="1">Carboplatin + Paclitaxel</td><td align="left" valign="middle" rowspan="1" colspan="1">Phase I completed</td><td align="left" valign="middle" rowspan="1" colspan="1">Ovarian</td><td align="left" valign="middle" rowspan="1" colspan="1">Recommended for phase II</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B110-cells-08-01013" ref-type="bibr">110</xref>]</td></tr><tr><td rowspan="2" align="left" valign="middle" style="border-right:solid thin;background:#F2F2F2" colspan="1"><bold>BCL-2</bold></td><td rowspan="2" align="left" valign="middle" style="background:#F2F2F2" colspan="1">Venetoclax</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Azacitidine</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">AML</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Elderly patients</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B111-cells-08-01013" ref-type="bibr">111</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Cyclophosphamide, etoposide, doxorubicin, methotrexate, 6-mercaptopurine, cytarabine</td><td align="left" valign="middle" rowspan="1" colspan="1">ALL</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" rowspan="1" colspan="1">Older patients with relapsed or refractory ALL</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B112-cells-08-01013" ref-type="bibr">112</xref>]</td></tr><tr><td rowspan="8" align="left" valign="middle" style="border-right:solid thin" colspan="1"><bold>CDK4/6</bold></td><td rowspan="2" align="left" valign="middle" style="background:#F2F2F2" colspan="1">Abemaciclib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Pemetrexed, or gemcitabine</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">NSCLC </td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">For stage IV patients</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B113-cells-08-01013" ref-type="bibr">113</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Temozolomide</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" rowspan="1" colspan="1">Glioblastoma</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B114-cells-08-01013" ref-type="bibr">114</xref>]</td></tr><tr><td rowspan="3" align="left" valign="middle" colspan="1">Palbociclib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Carboplatin</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Metastatic head and neck squamous cell carcinoma</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1"></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B115-cells-08-01013" ref-type="bibr">115</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Nab-paclitaxel </td><td align="left" valign="middle" rowspan="1" colspan="1">Phase I completed</td><td align="left" valign="middle" rowspan="1" colspan="1">mPDAC</td><td align="left" valign="middle" rowspan="1" colspan="1">No results posted; last update in May 30, 2019.</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B116-cells-08-01013" ref-type="bibr">116</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Temozolomide + irinotecan</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Solid tumors, neuroblastoma, medulloblastoma</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">For children, adolescents and young adults</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B117-cells-08-01013" ref-type="bibr">117</xref>]</td></tr><tr><td rowspan="3" align="left" valign="middle" colspan="1">Ribociclib</td><td align="left" valign="middle" rowspan="1" colspan="1">Docetaxel + Prednisone</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase Ib/II</td><td align="left" valign="middle" rowspan="1" colspan="1">mCRPC</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B118-cells-08-01013" ref-type="bibr">118</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Gemcitabine</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Malignant brain tumors</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1"></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B119-cells-08-01013" ref-type="bibr">119</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Paclitaxel + Carboplatin</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" rowspan="1" colspan="1">Ovarian cancer, fallopian tube cancer, peritoneal carcinoma</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B120-cells-08-01013" ref-type="bibr">120</xref>]</td></tr><tr><td rowspan="9" align="left" valign="middle" style="border-right:solid thin;background:#F2F2F2" colspan="1"><bold>DNA DAMAGE REPAIR</bold></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Niraparib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Temozolomide</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase Ib/II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">SCLC</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1"></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B121-cells-08-01013" ref-type="bibr">121</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Olaparib</td><td align="left" valign="middle" rowspan="1" colspan="1">Cisplatin</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" rowspan="1" colspan="1">Advanced NSCLC</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B122-cells-08-01013" ref-type="bibr">122</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Rucaparib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Irinotecan</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase Ib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Solid tumors</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">For patients with DNA repair defects in solid tumors</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B123-cells-08-01013" ref-type="bibr">123</xref>]</td></tr><tr><td rowspan="6" align="left" valign="middle" colspan="1">Veliparib</td><td rowspan="2" align="left" valign="middle" colspan="1">FOLFIRI</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" rowspan="1" colspan="1">Pancreatic (metastatic)</td><td align="left" valign="middle" rowspan="1" colspan="1">Second line therapy</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B124-cells-08-01013" ref-type="bibr">124</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Phase I completed</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Gastric</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Recommended for further investigation</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B124-cells-08-01013" ref-type="bibr">124</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Irinotecan</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" rowspan="1" colspan="1">Breast, lung, ovarian, pancreatic, Hodgkin’s lymphoma</td><td align="left" valign="middle" rowspan="1" colspan="1">For cancer that is metastatic or cannot be removed</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B125-cells-08-01013" ref-type="bibr">125</xref>]</td></tr><tr><td rowspan="2" align="left" valign="middle" style="background:#F2F2F2" colspan="1">Temozolomide</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">ALL</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1"></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B126-cells-08-01013" ref-type="bibr">126</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" rowspan="1" colspan="1">CRC</td><td align="left" valign="middle" rowspan="1" colspan="1">Recommended for further investigation</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B127-cells-08-01013" ref-type="bibr">127</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Topotecan</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Acute leukemias</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1"></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B128-cells-08-01013" ref-type="bibr">128</xref>]</td></tr><tr><td rowspan="6" align="left" valign="middle" style="border-right:solid thin" colspan="1"><bold>EGFR</bold></td><td rowspan="2" align="left" valign="middle" colspan="1">Cetuximab</td><td align="left" valign="middle" rowspan="1" colspan="1">FOLFIRI </td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" rowspan="1" colspan="1">CRC</td><td align="left" valign="middle" rowspan="1" colspan="1">For patients with FcγRIIIa polymorphism and wild-type KRAS, NRAS and BRAF</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B129-cells-08-01013" ref-type="bibr">129</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">FOLFOXIRI</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Locally advanced rectal carcinoma</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">For EGFR wild type patients</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B130-cells-08-01013" ref-type="bibr">130</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Necitumumab</td><td align="left" valign="middle" rowspan="1" colspan="1">Gemcitabine + Cisplatin </td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" rowspan="1" colspan="1">Stage IB, II or IIIA squamous NSCLC</td><td align="left" valign="middle" rowspan="1" colspan="1">Neoadjuvant therapy</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B131-cells-08-01013" ref-type="bibr">131</xref>]</td></tr><tr><td rowspan="2" align="left" valign="middle" style="background:#F2F2F2" colspan="1">Panitumumab</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">FOLFOX/FOLFIRI</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Liver (metastatic) </td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">For patients with wild-type KRAS; no results posted; last update May 14, 2019.</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B132-cells-08-01013" ref-type="bibr">132</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">mFOLFOX6 + bevacizumab/panitumumab</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase III</td><td align="left" valign="middle" rowspan="1" colspan="1">Advanced/recurrent CRC</td><td align="left" valign="middle" rowspan="1" colspan="1">First-line therapy for patients with KRAS/NRAS wild-type tumors</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B133-cells-08-01013" ref-type="bibr">133</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Pertuzumab</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Paclitaxel + Trastuzumab</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">HER2-positive breast cancer</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1"></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B134-cells-08-01013" ref-type="bibr">134</xref>]</td></tr><tr><td rowspan="6" align="left" valign="middle" style="border-right:solid thin" colspan="1"><bold>PI3K-AKT-MTOR</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">Copanlisib</td><td align="left" valign="middle" rowspan="1" colspan="1">Gemcitabine</td><td align="left" valign="middle" rowspan="1" colspan="1">Phase I completed</td><td align="left" valign="middle" rowspan="1" colspan="1">Cholangiocarcinoma</td><td align="left" valign="middle" rowspan="1" colspan="1">No results yet.</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B135-cells-08-01013" ref-type="bibr">135</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Duvelisib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Fludarabine + cyclophosphamide + rituximab (FCR)</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase Ib/II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">CLL</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1"></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B136-cells-08-01013" ref-type="bibr">136</xref>]</td></tr><tr><td rowspan="2" align="left" valign="middle" colspan="1">Everolimus</td><td align="left" valign="middle" rowspan="1" colspan="1">Carboplatin + Paclitaxel</td><td align="left" valign="middle" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="middle" rowspan="1" colspan="1">Everolimus failed to improve efficacy</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B137-cells-08-01013" ref-type="bibr">137</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Temozolomide</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Low-grade glioma </td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1"></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B138-cells-08-01013" ref-type="bibr">138</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Idelalisib</td><td align="left" valign="middle" rowspan="1" colspan="1">Bendamustine + Rituximab</td><td align="left" valign="middle" rowspan="1" colspan="1">Phase III completed</td><td align="left" valign="middle" rowspan="1" colspan="1">Relapsed or refractory CLL</td><td align="left" valign="middle" rowspan="1" colspan="1">Improved PFS but with serious adverse events and infections</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B139-cells-08-01013" ref-type="bibr">139</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Temsirolimus</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Carboplatin + Paclitaxel</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Recurrent or metastatic head and neck</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Recommended further investigation for PI3K/mTOR mutations</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B140-cells-08-01013" ref-type="bibr">140</xref>]</td></tr><tr><td rowspan="9" align="left" valign="middle" style="border-right:solid thin;border-bottom:solid thin" colspan="1"><bold>VEGF</bold></td><td rowspan="5" align="left" valign="middle" colspan="1">Bevacizumab</td><td align="left" valign="middle" rowspan="1" colspan="1">Capecitabine</td><td align="left" valign="middle" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" rowspan="1" colspan="1">Advanced or Metastatic Liver Cancer</td><td align="left" valign="middle" rowspan="1" colspan="1">"All patients presented serious adverse events; only 9.1% presented objective response"</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B141-cells-08-01013" ref-type="bibr">141</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Carboplatin + Paclitaxel (CPB)</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Recommended for phase III</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B142-cells-08-01013" ref-type="bibr">142</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Carboplatin + Paclitaxel + Everolimus (CPBE)</td><td align="left" valign="middle" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="middle" rowspan="1" colspan="1">Failed to improve PFS compared to CPB </td><td align="left" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">FOLFIRI (+ Onvansertib) </td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase Ib/II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">mCRC</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Second line therapy for patients with KRAS mutation</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B143-cells-08-01013" ref-type="bibr">143</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Temozolomide</td><td align="left" valign="middle" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" rowspan="1" colspan="1">Glioma (grade II/III)</td><td align="left" valign="middle" rowspan="1" colspan="1">Failed to improve 1-year OS</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B144-cells-08-01013" ref-type="bibr">144</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Lenvatinib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Paclitaxel</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Endometrial, ovarian, fallopian tube, or primary peritoneal cancer</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1"></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B145-cells-08-01013" ref-type="bibr">145</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Ramucirumab</td><td align="left" valign="middle" rowspan="1" colspan="1">FOLFIRI</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" rowspan="1" colspan="1">Gastric</td><td align="left" valign="middle" rowspan="1" colspan="1">For previous failed therapy </td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B146-cells-08-01013" ref-type="bibr">146</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Regorafenib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Irinotecan</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Metastatic gastro-esophageal adenocarcinomas</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Second line therapy</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B147-cells-08-01013" ref-type="bibr">147</xref>]</td></tr><tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sorafenib</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Irinotecan</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pediatric solid tumors</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Patients with mutations in Raf, PDGFR, VEGFR, Flt-3, KIT, JAK, STAT, RAS, MEK, or ERK</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B148-cells-08-01013" ref-type="bibr">148</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: OS—overall survival, FOLFIRI—folinic acid, 5-fluorouracil and irinotecan, FOLFIRINOX—folinic acid, 5-fluorouracil, irinotecan and oxaliplatin, CRC—colorectal cancer, mCRC—metastatic colorectal cancer, NSCLC—non-small cell lung cancer, SCLC—small cell lung cancer, ALL—acute lymphoblastic leukemia.</p></fn></table-wrap-foot></table-wrap><table-wrap id="cells-08-01013-t004" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-01013-t004_Table 4</object-id><label>Table 4</label><caption><p>Clinical trials with combinations between targeted therapies in which the first inhibit resistance mechanisms of the second.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin;border-right:solid thin" rowspan="1" colspan="1">Signalling Pathways</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Targeted Therapy</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Clinical Trial Phase</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Type of Tumor</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Rationale</th><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">References</th></tr></thead><tbody><tr><td rowspan="2" align="left" valign="middle" style="border-right:solid thin;background:#F2F2F2" colspan="1"><bold>ALK AND CDK4/6</bold></td><td rowspan="2" align="left" valign="middle" style="background:#F2F2F2" colspan="1">Ceritinib + Ribociclib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Phase I completed </td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">NSCLC</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">ALK+ NSCLC tumors</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B149-cells-08-01013" ref-type="bibr">149</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" rowspan="1" colspan="1">Neuroblastoma</td><td align="left" valign="middle" rowspan="1" colspan="1"><italic>In vitro</italic> synergy (lower phospho-RB1 levels only in ALK+ NB cells) </td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B150-cells-08-01013" ref-type="bibr">150</xref>,<xref rid="B151-cells-08-01013" ref-type="bibr">151</xref>]</td></tr><tr><td align="left" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1"><bold>MET AND AR</bold></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Crizotinib + Enzalutamide</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">mCRPC</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">AR inhibition upregulates MET (off-target effect for crizotinib)</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B152-cells-08-01013" ref-type="bibr">152</xref>,<xref rid="B153-cells-08-01013" ref-type="bibr">153</xref>]</td></tr><tr><td rowspan="2" align="left" valign="middle" style="border-right:solid thin" colspan="1"><bold>PDGFR AND C-SRC</bold></td><td rowspan="2" align="left" valign="middle" colspan="1">Crizotinib + Dasatinib</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" rowspan="1" colspan="1">Solid malignancies</td><td align="left" valign="middle" rowspan="1" colspan="1">Downstream effects of MET require c-Src, whose inhibition upregulates MET</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B154-cells-08-01013" ref-type="bibr">154</xref>,<xref rid="B155-cells-08-01013" ref-type="bibr">155</xref>]</td></tr><tr><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Phase I completed </td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">High-grade glioma</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">PDGFR upregulated in gliomas (off-target for dasatinib)</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B156-cells-08-01013" ref-type="bibr">156</xref>]</td></tr><tr><td align="left" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1"><bold>PI3K AND EGFR</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">Copanlisib + Cetuximab</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase Ib/II</td><td align="left" valign="middle" rowspan="1" colspan="1">HNSCC</td><td align="left" valign="middle" rowspan="1" colspan="1">Aberrant PI3K signaling confers resistance to cetuximab and both pathways are upregulated in HNSCC</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B157-cells-08-01013" ref-type="bibr">157</xref>,<xref rid="B158-cells-08-01013" ref-type="bibr">158</xref>]</td></tr><tr><td align="left" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1"><bold>VEGFR AND MTOR</bold></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Pazopanib + Everolimus</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase I</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Solid tumors</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">mTOR pathway activation confers resistance to anti-VEGF therapy</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B159-cells-08-01013" ref-type="bibr">159</xref>]</td></tr><tr><td align="left" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1"><bold>BCR</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">Idelalisib + Entospletinib</td><td align="left" valign="middle" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" rowspan="1" colspan="1">Lymphoid malignancies</td><td align="left" valign="middle" rowspan="1" colspan="1">Synergistic effect with simultaneous inhibition of multiple kinases in the BCR pathway (PI3K and Syk), but limited by severe life-threatening adverse effects.</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B160-cells-08-01013" ref-type="bibr">160</xref>]</td></tr><tr><td rowspan="2" align="left" valign="middle" style="border-right:solid thin;background:#F2F2F2" colspan="1"><bold>CDK4/6 AND PI3K/MTOR</bold></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Abemaciclib + LY3023414</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">PDAC</td><td rowspan="2" align="left" valign="middle" style="background:#F2F2F2" colspan="1">Enhanced PI3K/mTOR activity confers resistance to CDKi therapy</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B161-cells-08-01013" ref-type="bibr">161</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Ribociclib + Everolimus</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" rowspan="1" colspan="1">mPDAC</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B105-cells-08-01013" ref-type="bibr">105</xref>]</td></tr><tr><td align="left" valign="middle" style="border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1"><bold>CDK4/6 AND EGFR</bold></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Palbociclib + Cetuximab</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">HNSCC</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">EGFR overexpression is an oncogenic driver and there is either a frequent loss of CDKN2A or amplification of CCND1</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B162-cells-08-01013" ref-type="bibr">162</xref>]</td></tr><tr><td align="left" valign="middle" style="border-right:solid thin" rowspan="1" colspan="1"><bold>CDK4/6 AND MEK</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">Palbociclib + Trametinib</td><td align="left" valign="middle" rowspan="1" colspan="1">Phase Ib completed</td><td align="left" valign="middle" rowspan="1" colspan="1">Advanced solid malignancies</td><td align="left" valign="middle" rowspan="1" colspan="1">CDK activity confers resistance to MEKi </td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B163-cells-08-01013" ref-type="bibr">163</xref>,<xref rid="B164-cells-08-01013" ref-type="bibr">164</xref>]</td></tr><tr><td rowspan="2" align="left" valign="middle" style="border-right:solid thin;background:#F2F2F2" colspan="1"><bold>BRAF AND MEK</bold></td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Dabrafenib + Trametinib</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">Ongoing phase II</td><td rowspan="2" align="left" valign="middle" style="background:#F2F2F2" colspan="1">Melanoma and brain metastases</td><td rowspan="2" align="left" valign="middle" style="background:#F2F2F2" colspan="1">MAPK pathway reactivation confers resistance to BRAFi. Melanoma brain metastasis seem to lack ABCB1 expression. Combination can cross blood-brain barrier.</td><td align="left" valign="middle" style="background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B165-cells-08-01013" ref-type="bibr">165</xref>]</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Vemurafenib + Cobimetinib</td><td align="left" valign="middle" rowspan="1" colspan="1">Ongoing phase II</td><td align="left" valign="middle" rowspan="1" colspan="1">[<xref rid="B166-cells-08-01013" ref-type="bibr">166</xref>]</td></tr><tr><td align="left" valign="middle" style="border-bottom:solid thin;border-right:solid thin;background:#F2F2F2" rowspan="1" colspan="1"><bold>VEGFR AND EGFR</bold></td><td align="left" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" rowspan="1" colspan="1">Bevacizumab + Erlotinib</td><td align="left" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" rowspan="1" colspan="1">Phase II completed</td><td align="left" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" rowspan="1" colspan="1">Advanced or Metastatic Liver Cancer</td><td align="left" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" rowspan="1" colspan="1">Dual blockade of tumor neovascularization and proliferative signaling.</td><td align="left" valign="middle" style="border-bottom:solid thin;background:#F2F2F2" rowspan="1" colspan="1">[<xref rid="B167-cells-08-01013" ref-type="bibr">167</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: HNSCC - Head and neck squamous cell carcinoma, mCRPC - metastatic castration-resistant prostate cancer, mPDAC - metastatic pancreatic duct adenocarcinoma, NSCLC - non-small cell lung cancer, PDAC - Pancreatic duct adenocarcinoma.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000924 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000924 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= ChloroquineV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé=
|texte=
}}
| This area was generated with Dilib version V0.6.33. |  |