Highlights in Resistance Mechanism Pathways for Combination Therapy
Identifieur interne : 000720 ( Pmc/Checkpoint ); précédent : 000719; suivant : 000721Highlights in Resistance Mechanism Pathways for Combination Therapy
Auteurs : João M. A. Delou ; Alana S. O. Souza ; Leonel C. M. Souza ; Helena L. BorgesSource :
- Cells [ 2073-4409 ] ; 2019.
Abstract
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.
Url:
DOI: 10.3390/cells8091013
PubMed: 31480389
PubMed Central: 6770082
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<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><idno type="wicri:Area/Pmc/Curation">000924</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000924</idno><idno type="wicri:Area/Pmc/Checkpoint">000720</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000720</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. 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<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><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><affiliations><list></list><tree><noCountry><name sortKey="Borges, Helena L" sort="Borges, Helena L" uniqKey="Borges H" first="Helena L." last="Borges">Helena L. Borges</name><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><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><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></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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