Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors.
Identifieur interne : 000000 ( PubMed/Curation ); suivant : 000001Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors.
Auteurs : Tan-Min Chin [Singapour] ; Gandhi T K. Boopathy [Singapour] ; Ellen P S. Man [Singapour] ; John G. Clohessy [États-Unis] ; Eva Csizmadia [États-Unis] ; Margaret P. Quinlan [États-Unis] ; Thomas Putti ; Seow-Ching Wan [Singapour] ; Chen Xie [Singapour] ; Azhar Ali [Singapour] ; Fhu Chee Wai [Singapour] ; Yan Shan Ong ; Boon-Cher Goh [Singapour] ; Jeff Settleman [États-Unis] ; Wanjin Hong ; Elena Levantini [États-Unis] ; Daniel G. Tenen [Singapour]Source :
- Theranostics [ 1838-7640 ] ; 2020.
Abstract
Oncogene-addicted cancers are predominantly driven by specific oncogenic pathways and display initial exquisite sensitivity to designer therapies, but eventually become refractory to treatments. Clear understanding of lung tumorigenic mechanisms is essential for improved therapies. Methods: Lysosomes were analyzed in EGFR-WT and mutant cells and corresponding patient samples using immunofluorescence or immunohistochemistry and immunoblotting. Microtubule organization and dynamics were studied using immunofluorescence analyses. Also, we have validated our findings in a transgenic mouse model that contain EGFR-TKI resistant mutations. Results: We herein describe a novel mechanism that a mutated kinase disrupts the microtubule organization and results in a defective endosomal/lysosomal pathway. This prevents the efficient degradation of phosphorylated proteins that become trapped within the endosomes and continue to signal, therefore amplifying downstream proliferative and survival pathways. Phenotypically, a distinctive subcellular appearance of LAMP1 secondary to microtubule dysfunction in cells expressing EGFR kinase mutants is seen, and this may have potential diagnostic applications for the detection of such mutants. We demonstrate that lysosomal-inhibitors re-sensitize resistant cells to EGFR tyrosine-kinase inhibitors (TKIs). Identifying the endosome-lysosome pathway and microtubule dysfunction as a mechanism of resistance allows to pharmacologically intervene on this pathway. Conclusions: We find that the combination of microtubule stabilizing agent and lysosome inhibitor could reduce the tumor progression in EGFR TKI resistant mouse models of lung cancer.
DOI: 10.7150/thno.38729
PubMed: 32194831
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Thomas Putti<affiliation><nlm:affiliation>National University Health System, 5 Lower Kent Ridge Road, Singapore 119074.</nlm:affiliation><wicri:noCountry code="subField">Singapore 119074</wicri:noCountry></affiliation><affiliation><nlm:affiliation>Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Proteos, Singapore 138673.</nlm:affiliation><wicri:noCountry code="subField">Singapore 138673</wicri:noCountry></affiliation><affiliation><nlm:affiliation>Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Proteos, Singapore 138673.</nlm:affiliation><wicri:noCountry code="subField">Singapore 138673</wicri:noCountry></affiliation>Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors.</title><author><name sortKey="Chin, Tan Min" sort="Chin, Tan Min" uniqKey="Chin T" first="Tan-Min" last="Chin">Tan-Min Chin</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Boopathy, Gandhi T K" sort="Boopathy, Gandhi T K" uniqKey="Boopathy G" first="Gandhi T K" last="Boopathy">Gandhi T K. 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Quinlan</name><affiliation wicri:level="2"><nlm:affiliation>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown</wicri:cityArea></affiliation></author><author><name sortKey="Putti, Thomas" sort="Putti, Thomas" uniqKey="Putti T" first="Thomas" last="Putti">Thomas Putti</name><affiliation><nlm:affiliation>National University Health System, 5 Lower Kent Ridge Road, Singapore 119074.</nlm:affiliation><wicri:noCountry code="subField">Singapore 119074</wicri:noCountry></affiliation></author><author><name sortKey="Wan, Seow Ching" sort="Wan, Seow Ching" uniqKey="Wan S" first="Seow-Ching" last="Wan">Seow-Ching Wan</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Xie, Chen" sort="Xie, Chen" uniqKey="Xie C" first="Chen" last="Xie">Chen Xie</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Ali, Azhar" sort="Ali, Azhar" uniqKey="Ali A" first="Azhar" last="Ali">Azhar Ali</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Wai, Fhu Chee" sort="Wai, Fhu Chee" uniqKey="Wai F" first="Fhu Chee" last="Wai">Fhu Chee Wai</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Ong, Yan Shan" sort="Ong, Yan Shan" uniqKey="Ong Y" first="Yan Shan" last="Ong">Yan Shan Ong</name><affiliation><nlm:affiliation>Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Proteos, Singapore 138673.</nlm:affiliation><wicri:noCountry code="subField">Singapore 138673</wicri:noCountry></affiliation></author><author><name sortKey="Goh, Boon Cher" sort="Goh, Boon Cher" uniqKey="Goh B" first="Boon-Cher" last="Goh">Boon-Cher Goh</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Settleman, Jeff" sort="Settleman, Jeff" uniqKey="Settleman J" first="Jeff" last="Settleman">Jeff Settleman</name><affiliation wicri:level="2"><nlm:affiliation>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown</wicri:cityArea></affiliation></author><author><name sortKey="Hong, Wanjin" sort="Hong, Wanjin" uniqKey="Hong W" first="Wanjin" last="Hong">Wanjin Hong</name><affiliation><nlm:affiliation>Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Proteos, Singapore 138673.</nlm:affiliation><wicri:noCountry code="subField">Singapore 138673</wicri:noCountry></affiliation></author><author><name sortKey="Levantini, Elena" sort="Levantini, Elena" uniqKey="Levantini E" first="Elena" last="Levantini">Elena Levantini</name><affiliation wicri:level="2"><nlm:affiliation>Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Harvard Stem Cell Institute, Harvard Medical School, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Tenen, Daniel G" sort="Tenen, Daniel G" uniqKey="Tenen D" first="Daniel G" last="Tenen">Daniel G. Tenen</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32194831</idno><idno type="pmid">32194831</idno><idno type="doi">10.7150/thno.38729</idno><idno type="wicri:Area/PubMed/Corpus">000000</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000000</idno><idno type="wicri:Area/PubMed/Curation">000000</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000000</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors.</title><author><name sortKey="Chin, Tan Min" sort="Chin, Tan Min" uniqKey="Chin T" first="Tan-Min" last="Chin">Tan-Min Chin</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Boopathy, Gandhi T K" sort="Boopathy, Gandhi T K" uniqKey="Boopathy G" first="Gandhi T K" last="Boopathy">Gandhi T K. Boopathy</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Man, Ellen P S" sort="Man, Ellen P S" uniqKey="Man E" first="Ellen P S" last="Man">Ellen P S. Man</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Clohessy, John G" sort="Clohessy, John G" uniqKey="Clohessy J" first="John G" last="Clohessy">John G. Clohessy</name><affiliation wicri:level="2"><nlm:affiliation>Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Harvard Stem Cell Institute, Harvard Medical School, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Csizmadia, Eva" sort="Csizmadia, Eva" uniqKey="Csizmadia E" first="Eva" last="Csizmadia">Eva Csizmadia</name><affiliation wicri:level="2"><nlm:affiliation>Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Harvard Stem Cell Institute, Harvard Medical School, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Quinlan, Margaret P" sort="Quinlan, Margaret P" uniqKey="Quinlan M" first="Margaret P" last="Quinlan">Margaret P. Quinlan</name><affiliation wicri:level="2"><nlm:affiliation>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown</wicri:cityArea></affiliation></author><author><name sortKey="Putti, Thomas" sort="Putti, Thomas" uniqKey="Putti T" first="Thomas" last="Putti">Thomas Putti</name><affiliation><nlm:affiliation>National University Health System, 5 Lower Kent Ridge Road, Singapore 119074.</nlm:affiliation><wicri:noCountry code="subField">Singapore 119074</wicri:noCountry></affiliation></author><author><name sortKey="Wan, Seow Ching" sort="Wan, Seow Ching" uniqKey="Wan S" first="Seow-Ching" last="Wan">Seow-Ching Wan</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Xie, Chen" sort="Xie, Chen" uniqKey="Xie C" first="Chen" last="Xie">Chen Xie</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Ali, Azhar" sort="Ali, Azhar" uniqKey="Ali A" first="Azhar" last="Ali">Azhar Ali</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Wai, Fhu Chee" sort="Wai, Fhu Chee" uniqKey="Wai F" first="Fhu Chee" last="Wai">Fhu Chee Wai</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Ong, Yan Shan" sort="Ong, Yan Shan" uniqKey="Ong Y" first="Yan Shan" last="Ong">Yan Shan Ong</name><affiliation><nlm:affiliation>Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Proteos, Singapore 138673.</nlm:affiliation><wicri:noCountry code="subField">Singapore 138673</wicri:noCountry></affiliation></author><author><name sortKey="Goh, Boon Cher" sort="Goh, Boon Cher" uniqKey="Goh B" first="Boon-Cher" last="Goh">Boon-Cher Goh</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author><author><name sortKey="Settleman, Jeff" sort="Settleman, Jeff" uniqKey="Settleman J" first="Jeff" last="Settleman">Jeff Settleman</name><affiliation wicri:level="2"><nlm:affiliation>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown</wicri:cityArea></affiliation></author><author><name sortKey="Hong, Wanjin" sort="Hong, Wanjin" uniqKey="Hong W" first="Wanjin" last="Hong">Wanjin Hong</name><affiliation><nlm:affiliation>Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Proteos, Singapore 138673.</nlm:affiliation><wicri:noCountry code="subField">Singapore 138673</wicri:noCountry></affiliation></author><author><name sortKey="Levantini, Elena" sort="Levantini, Elena" uniqKey="Levantini E" first="Elena" last="Levantini">Elena Levantini</name><affiliation wicri:level="2"><nlm:affiliation>Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Harvard Stem Cell Institute, Harvard Medical School, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Tenen, Daniel G" sort="Tenen, Daniel G" uniqKey="Tenen D" first="Daniel G" last="Tenen">Daniel G. Tenen</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:affiliation><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author></analytic><series><title level="j">Theranostics</title><idno type="eISSN">1838-7640</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Oncogene-addicted cancers are predominantly driven by specific oncogenic pathways and display initial exquisite sensitivity to designer therapies, but eventually become refractory to treatments. Clear understanding of lung tumorigenic mechanisms is essential for improved therapies. <b>Methods</b>: Lysosomes were analyzed in EGFR-WT and mutant cells and corresponding patient samples using immunofluorescence or immunohistochemistry and immunoblotting. Microtubule organization and dynamics were studied using immunofluorescence analyses. Also, we have validated our findings in a transgenic mouse model that contain EGFR-TKI resistant mutations. <b>Results</b>: We herein describe a novel mechanism that a mutated kinase disrupts the microtubule organization and results in a defective endosomal/lysosomal pathway. This prevents the efficient degradation of phosphorylated proteins that become trapped within the endosomes and continue to signal, therefore amplifying downstream proliferative and survival pathways. Phenotypically, a distinctive subcellular appearance of LAMP1 secondary to microtubule dysfunction in cells expressing EGFR kinase mutants is seen, and this may have potential diagnostic applications for the detection of such mutants. We demonstrate that lysosomal-inhibitors re-sensitize resistant cells to EGFR tyrosine-kinase inhibitors (TKIs). Identifying the endosome-lysosome pathway and microtubule dysfunction as a mechanism of resistance allows to pharmacologically intervene on this pathway. <b>Conclusions</b>: We find that the combination of microtubule stabilizing agent and lysosome inhibitor could reduce the tumor progression in EGFR TKI resistant mouse models of lung cancer.</div></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">32194831</PMID><DateRevised><Year>2020</Year><Month>03</Month><Day>23</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1838-7640</ISSN><JournalIssue CitedMedium="Internet"><Volume>10</Volume><Issue>6</Issue><PubDate><Year>2020</Year></PubDate></JournalIssue><Title>Theranostics</Title><ISOAbbreviation>Theranostics</ISOAbbreviation></Journal><ArticleTitle>Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors.</ArticleTitle><Pagination><MedlinePgn>2727-2743</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.7150/thno.38729</ELocationID><Abstract><AbstractText>Oncogene-addicted cancers are predominantly driven by specific oncogenic pathways and display initial exquisite sensitivity to designer therapies, but eventually become refractory to treatments. Clear understanding of lung tumorigenic mechanisms is essential for improved therapies. <b>Methods</b>: Lysosomes were analyzed in EGFR-WT and mutant cells and corresponding patient samples using immunofluorescence or immunohistochemistry and immunoblotting. Microtubule organization and dynamics were studied using immunofluorescence analyses. Also, we have validated our findings in a transgenic mouse model that contain EGFR-TKI resistant mutations. <b>Results</b>: We herein describe a novel mechanism that a mutated kinase disrupts the microtubule organization and results in a defective endosomal/lysosomal pathway. This prevents the efficient degradation of phosphorylated proteins that become trapped within the endosomes and continue to signal, therefore amplifying downstream proliferative and survival pathways. Phenotypically, a distinctive subcellular appearance of LAMP1 secondary to microtubule dysfunction in cells expressing EGFR kinase mutants is seen, and this may have potential diagnostic applications for the detection of such mutants. We demonstrate that lysosomal-inhibitors re-sensitize resistant cells to EGFR tyrosine-kinase inhibitors (TKIs). Identifying the endosome-lysosome pathway and microtubule dysfunction as a mechanism of resistance allows to pharmacologically intervene on this pathway. <b>Conclusions</b>: We find that the combination of microtubule stabilizing agent and lysosome inhibitor could reduce the tumor progression in EGFR TKI resistant mouse models of lung cancer.</AbstractText><CopyrightInformation>© The author(s).</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Chin</LastName><ForeName>Tan-Min</ForeName><Initials>TM</Initials><AffiliationInfo><Affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>National University Health System, 5 Lower Kent Ridge Road, Singapore 119074.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Parkway Cancer Centre, Gleneagles Hospital. 6A Napier Road, Singapore 258500.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Boopathy</LastName><ForeName>Gandhi T K</ForeName><Initials>GTK</Initials><AffiliationInfo><Affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Proteos, Singapore 138673.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Man</LastName><ForeName>Ellen P S</ForeName><Initials>EPS</Initials><AffiliationInfo><Affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Clohessy</LastName><ForeName>John G</ForeName><Initials>JG</Initials><AffiliationInfo><Affiliation>Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Csizmadia</LastName><ForeName>Eva</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Quinlan</LastName><ForeName>Margaret P</ForeName><Initials>MP</Initials><AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Putti</LastName><ForeName>Thomas</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>National University Health System, 5 Lower Kent Ridge Road, Singapore 119074.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wan</LastName><ForeName>Seow-Ching</ForeName><Initials>SC</Initials><AffiliationInfo><Affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xie</LastName><ForeName>Chen</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ali</LastName><ForeName>Azhar</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wai</LastName><ForeName>Fhu Chee</ForeName><Initials>FC</Initials><AffiliationInfo><Affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ong</LastName><ForeName>Yan Shan</ForeName><Initials>YS</Initials><AffiliationInfo><Affiliation>Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Proteos, Singapore 138673.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Goh</LastName><ForeName>Boon-Cher</ForeName><Initials>BC</Initials><AffiliationInfo><Affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>National University Health System, 5 Lower Kent Ridge Road, Singapore 119074.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Settleman</LastName><ForeName>Jeff</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Current address for Jeff Settleman: Pfizer, Inc. 10646 Science Center Drive, San Diego, CA 92121.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hong</LastName><ForeName>Wanjin</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Proteos, Singapore 138673.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Levantini</LastName><ForeName>Elena</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tenen</LastName><ForeName>Daniel G</ForeName><Initials>DG</Initials><AffiliationInfo><Affiliation>Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P01 HL131477</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R35 CA197697</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>02</Month><Day>03</Day></ArticleDate></Article><MedlineJournalInfo><Country>Australia</Country><MedlineTA>Theranostics</MedlineTA><NlmUniqueID>101552395</NlmUniqueID><ISSNLinking>1838-7640</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">EGFR mutants</Keyword><Keyword MajorTopicYN="N">NSCLC</Keyword><Keyword MajorTopicYN="N">chloroquine</Keyword><Keyword MajorTopicYN="N">microtubule dysfunction</Keyword><Keyword MajorTopicYN="N">tyrosine kinase inhibitors</Keyword></KeywordList><CoiStatement>Competing Interests: The authors have declared that no competing interest exists.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>07</Month><Day>25</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>11</Month><Day>24</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>3</Month><Day>21</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>3</Month><Day>21</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>3</Month><Day>21</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId 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