Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors
Identifieur interne : 000030 ( Pmc/Checkpoint ); précédent : 000029; suivant : 000031Targeting 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, Italie] ; Daniel G. Tenen [Singapour, États-Unis]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.
Url:
DOI: 10.7150/thno.38729
PubMed: 32194831
PubMed Central: 7052910
Affiliations:
- Italie, Singapour, États-Unis
- Californie, Massachusetts, Toscane
- Pise
- Université nationale de Singapour
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors</title>
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<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>
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<author><name sortKey="Clohessy, John G" sort="Clohessy, John G" uniqKey="Clohessy J" first="John G." last="Clohessy">John G. Clohessy</name>
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<author><name sortKey="Quinlan, Margaret P" sort="Quinlan, Margaret P" uniqKey="Quinlan M" first="Margaret P" last="Quinlan">Margaret P. Quinlan</name>
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<placeName><region type="state">Massachusetts</region>
</placeName>
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<author><name sortKey="Putti, Thomas" sort="Putti, Thomas" uniqKey="Putti T" first="Thomas" last="Putti">Thomas Putti</name>
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<wicri:noCountry code="subfield">Singapore 119074.</wicri:noCountry>
</affiliation>
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<author><name sortKey="Wan, Seow Ching" sort="Wan, Seow Ching" uniqKey="Wan S" first="Seow-Ching" last="Wan">Seow-Ching Wan</name>
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<orgName type="university">Université nationale de Singapour</orgName>
<country>Singapour</country>
</affiliation>
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<author><name sortKey="Xie, Chen" sort="Xie, Chen" uniqKey="Xie C" first="Chen" last="Xie">Chen Xie</name>
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<orgName type="university">Université nationale de Singapour</orgName>
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<author><name sortKey="Ali, Azhar" sort="Ali, Azhar" uniqKey="Ali A" first="Azhar" last="Ali">Azhar Ali</name>
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<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:aff id="A1">Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:aff>
<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:aff id="A4">Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673.</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138673.</wicri:noCountry>
</affiliation>
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<author><name sortKey="Goh, Boon Cher" sort="Goh, Boon Cher" uniqKey="Goh B" first="Boon-Cher" last="Goh">Boon-Cher Goh</name>
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<orgName type="university">Université nationale de Singapour</orgName>
<country>Singapour</country>
</affiliation>
<affiliation><nlm:aff id="A2">National University Health System, 5 Lower Kent Ridge Road, Singapore 119074.</nlm:aff>
<wicri:noCountry code="subfield">Singapore 119074.</wicri:noCountry>
</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:aff id="A6">Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129.</nlm:aff>
<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>
<affiliation wicri:level="2"><nlm:aff id="A8">Current address for Jeff Settleman: Pfizer, Inc. 10646 Science Center Drive, San Diego, CA 92121</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>Current address for Jeff Settleman: Pfizer, Inc. 10646 Science Center Drive, San Diego</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Hong, Wanjin" sort="Hong, Wanjin" uniqKey="Hong W" first="Wanjin" last="Hong">Wanjin Hong</name>
<affiliation><nlm:aff id="A4">Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673.</nlm:aff>
<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:aff id="A5">Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</nlm:aff>
<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>
<affiliation wicri:level="3"><nlm:aff id="A7">Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Italie</country>
<wicri:regionArea>Institute of Biomedical Technologies, National Research Council (CNR), Pisa</wicri:regionArea>
<placeName><settlement type="city">Pise</settlement>
<region nuts="2">Toscane</region>
</placeName>
</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:aff id="A1">Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</nlm:aff>
<orgName type="university">Université nationale de Singapour</orgName>
<country>Singapour</country>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A5">Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</nlm:aff>
<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>
</analytic>
<series><title level="j">Theranostics</title>
<idno type="eISSN">1838-7640</idno>
<imprint><date when="2020">2020</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><p>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.</p>
<p><bold>Methods</bold>
: 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.</p>
<p><bold>Results</bold>
: 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.</p>
<p><bold>Conclusions</bold>
: 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.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Weinstein, Ib" uniqKey="Weinstein I">IB Weinstein</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="Mellman, I" uniqKey="Mellman I">I Mellman</name>
</author>
<author><name sortKey="Yarden, Y" uniqKey="Yarden Y">Y Yarden</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sorkin, A" uniqKey="Sorkin A">A Sorkin</name>
</author>
<author><name sortKey="Von Zastrow, M" uniqKey="Von Zastrow M">M von Zastrow</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mosesson, Y" uniqKey="Mosesson Y">Y Mosesson</name>
</author>
<author><name sortKey="Mills, Gb" uniqKey="Mills G">GB Mills</name>
</author>
<author><name sortKey="Yarden, Y" uniqKey="Yarden Y">Y Yarden</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Waterman, H" uniqKey="Waterman H">H Waterman</name>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Theranostics</journal-id>
<journal-id journal-id-type="iso-abbrev">Theranostics</journal-id>
<journal-id journal-id-type="publisher-id">thno</journal-id>
<journal-title-group><journal-title>Theranostics</journal-title>
</journal-title-group>
<issn pub-type="epub">1838-7640</issn>
<publisher><publisher-name>Ivyspring International Publisher</publisher-name>
<publisher-loc>Sydney</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">32194831</article-id>
<article-id pub-id-type="pmc">7052910</article-id>
<article-id pub-id-type="doi">10.7150/thno.38729</article-id>
<article-id pub-id-type="publisher-id">thnov10p2727</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject>
</subj-group>
</article-categories>
<title-group><article-title>Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Chin</surname>
<given-names>Tan-Min</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="author-notes" rid="FNA_star">*</xref>
<xref ref-type="corresp" rid="FNA_envelop">✉</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Boopathy</surname>
<given-names>Gandhi T. K.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A4">4</xref>
<xref ref-type="author-notes" rid="FNA_star">*</xref>
<xref ref-type="corresp" rid="FNA_envelop">✉</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Man</surname>
<given-names>Ellen P.S.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Clohessy</surname>
<given-names>John G.</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Csizmadia</surname>
<given-names>Eva</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Quinlan</surname>
<given-names>Margaret P</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Putti</surname>
<given-names>Thomas</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wan</surname>
<given-names>Seow-Ching</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Xie</surname>
<given-names>Chen</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ali</surname>
<given-names>Azhar</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wai</surname>
<given-names>Fhu Chee</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ong</surname>
<given-names>Yan Shan</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Goh</surname>
<given-names>Boon-Cher</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Settleman</surname>
<given-names>Jeff</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
<xref ref-type="aff" rid="A8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hong</surname>
<given-names>Wanjin</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Levantini</surname>
<given-names>Elena</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
<xref ref-type="aff" rid="A7">7</xref>
<xref ref-type="author-notes" rid="FNA_number">#</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tenen</surname>
<given-names>Daniel G.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A5">5</xref>
<xref ref-type="author-notes" rid="FNA_number">#</xref>
<xref ref-type="corresp" rid="FNA_envelop">✉</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599.</aff>
<aff id="A2"><label>2</label>
National University Health System, 5 Lower Kent Ridge Road, Singapore 119074.</aff>
<aff id="A3"><label>3</label>
Parkway Cancer Centre, Gleneagles Hospital. 6A Napier Road, Singapore 258500.</aff>
<aff id="A4"><label>4</label>
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673.</aff>
<aff id="A5"><label>5</label>
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.</aff>
<aff id="A6"><label>6</label>
Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, MA 02129.</aff>
<aff id="A7"><label>7</label>
Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy.</aff>
<aff id="A8"><label>8</label>
Current address for Jeff Settleman: Pfizer, Inc. 10646 Science Center Drive, San Diego, CA 92121</aff>
<author-notes><corresp id="FNA_envelop">✉ Corresponding authors: Lead contact: Daniel G. Tenen (E-mail: <email>daniel.tenen@nus.edu.sg</email>
); Tan Min Chin (E-mail: <email>csictm@nus.edu.sg</email>
); Gandhi T. K. Boopathy (E-mail: <email>gandhibtk@imcb.a-star.edu.sg</email>
)</corresp>
<fn fn-type="equal" id="FNA_star"><p>* These authors contributed equally</p>
</fn>
<fn fn-type="equal" id="FNA_number"><p># These authors contributed equally</p>
</fn>
<fn fn-type="COI-statement"><p>Competing Interests: The authors have declared that no competing interest exists.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2020</year>
</pub-date>
<pub-date pub-type="epub"><day>3</day>
<month>2</month>
<year>2020</year>
</pub-date>
<volume>10</volume>
<issue>6</issue>
<fpage>2727</fpage>
<lpage>2743</lpage>
<history><date date-type="received"><day>25</day>
<month>7</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>24</day>
<month>11</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The author(s)</copyright-statement>
<copyright-year>2020</copyright-year>
<license license-type="open-access"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>
). See <ext-link ext-link-type="uri" xlink:href="http://ivyspring.com/terms">http://ivyspring.com/terms</ext-link>
for full terms and conditions.</license-p>
</license>
</permissions>
<abstract><p>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.</p>
<p><bold>Methods</bold>
: 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.</p>
<p><bold>Results</bold>
: 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.</p>
<p><bold>Conclusions</bold>
: 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.</p>
</abstract>
<kwd-group><kwd>NSCLC</kwd>
<kwd>EGFR mutants</kwd>
<kwd>tyrosine kinase inhibitors</kwd>
<kwd>chloroquine</kwd>
<kwd>microtubule dysfunction</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="F1" position="float"><label>Figure 1</label>
<caption><p><bold> Differential distribution of acidic and lysosomal organelles in EGFR wild-type versus mutant NSCLC cell lines and tumors. A</bold>
. Micrographs of EGFR wild-type (H1299 and H1666) and mutant (PC9 and H1650) NSCLC cells stained with acridine orange (green and orange) and lysotracker (blue). <bold>B.</bold>
H1299 and PC9 cells were immunostained using antibodies specific for early endosomes (EEA1 and Rab5), late endosomes/lysosomes (Rab7 and LAMP1), and recycling endosomes (Rab11). The images represent maximum intensity projections using confocal microscopy. DAPI (blue) stains the nucleus. Scale bar: 10 μm. <bold>C.</bold>
Immunohistochemical stains of LAMP1 and EGFR in primary human lung cancers. Staining demonstrates that the distribution of LAMP1 and EGFR (brown) in tumors closely resembles the distribution observed in NSCLC cell lines. Scale bar: 25 μm <bold>D.</bold>
Western blot analysis of LAMP1 expression in NSCLC EGFR wild-type and mutant cell lines. Whole cell lysates were prepared, immunoblotted for early endosomes (EEA1), lysosomes (LAMP1) and loading controls (GAPDH and β-Actin).</p>
</caption>
<graphic xlink:href="thnov10p2727g001"></graphic>
</fig>
<fig id="F2" position="float"><label>Figure 2</label>
<caption><p><bold> EGFR mutants display delayed degradation of activated signals, resulting in increased and prolonged phosphorylated EGFR signaling. A.</bold>
EGFR degradation assay was performed on H1299 (EGFR-WT) and PC9 (EGFR-19del) lung cancer cells and cell lysates were immunoblotted for pY1068-EGFR, pY1045-EGFR, total EGFR and β-actin (as a loading control). EGFR degradation assay was performed and processed for immunofluorescence using the following cells and conditions: (<bold>B</bold>
) LAMP1 antibody (red) for lysosomes and EGF (green) in H1299 and PC9 cells, (<bold>C</bold>
) LAMP1 antibody (green) for lysosomes and EGF (purple) in and H1299-stable cells with EGFR-WT or EGFR-L858R (<bold>D</bold>
) EEA1 antibody (red) for early endosomes and EGF (green) in H1299 and PC9 cells. The white arrows point colocalization of EGF with LAMP1 or EEA1. <bold>E.</bold>
Quantitation of the fluorescent EGF intensity (green) overlapping with LAMP1 staining in panel B (top) or EEA1 staining in panel D (bottom) in H1299 (green line) and PC9 cells (red line) were plotted. Overlapping signal intensities were calculated using Image J. An average data of more than 100 cells from three independent experiments for each time point are plotted. Error bars represent standard deviation from the mean. ** and *** indicates <italic>p</italic>
<0.001 and <italic>p</italic>
<0.0001, respectively. <bold>F.</bold>
Western blot and immunofluorescence studies on H1299 cell line and after knockdown of SNX1 (top blots and micrographs) and after transfection of SNX1 in PC9 cells (bottom blots and micrographs). Scale bar: 10 μm.</p>
</caption>
<graphic xlink:href="thnov10p2727g002"></graphic>
</fig>
<fig id="F3" position="float"><label>Figure 3</label>
<caption><p><bold> EGFR mutants cause disruption of the microtubule network. A.</bold>
EGFR mutants have disorganized microtubule network. Immunofluorescence of β-Tubulin in EGFR wild type (NCI-H1299, NCI-H1666, and A431) and mutant cells (PC9, HCC827, HCC4006 and H1975). EGFR signaling stimulates microtubule organization. Pulse chasing of fluorescently labelled EGF was performed on the following conditions: (<bold>B</bold>
) H1299 and PC9 cells with EGF (green) and subsequently processed for immunofluorescence using β-tubulin antibody (red). C, H1299 cells were stably transfected with EGFR-WT or EGFR-L858R were treated with EGF (purple) and subsequently processed for immunofluorescence using β-tubulin antibody (green). White arrows point to microtubule organizing center. DAPI stains nucleus. Scale bar: 10 μm.</p>
</caption>
<graphic xlink:href="thnov10p2727g003"></graphic>
</fig>
<fig id="F4" position="float"><label>Figure 4</label>
<caption><p><bold> Loss of EGFR mutant or its kinase activity causes microtubule re-organization. A.</bold>
Protein expression analysis of EGFR, endocytic proteins and β-Tubulin (for loading control) using immunoblot of H1650 cells with control siRNA and EGFR siRNA (left); Densitometry of percent of EGFR protein expressions were normalized to β-actin (right). <bold>B.</bold>
Immunofluorescence of β-Tubulin (green) in control and EGFR mutant knockdown in H1650 cells. <bold>C.</bold>
Immunofluorescence of EGFR and endocytic markers in control and EGFR knockdown in PC9 cells. White arrows point to perinuclear localization. <bold>D.</bold>
Microtubule organization in EGFR mutant PC9 cells: Immunofluorescence staining of β-Tubulin and LAMP1 in control or EGFR knockdown or EGFR knockdown cells treated with 30 μM nocodazole. <bold>E.</bold>
Erlotinib treatment of PC9 cells recovers microtubule organization and lysosomal localization: PC9 cells were treated with DMSO or 50 nM Erlotinib. Cells were fixed and analyzed for β-tubulin, pY1068-EGFR, and LAMP1 by immunofluorescence. White arrows point towards the microtubule organizing center (MTOC). Samples were recorded using confocal microscopy and represented in maximum intensity projections. DAPI stain indicates the nucleus (blue). Scale bar: 10 μm. <bold>F.</bold>
Immunohistochemical studies on LAMP1 in EGFR mutant tumors pre- and post-EGFR TKI treatment, on the left and right, respectively. The LAMP1 distribution was studied in two paired patient tumor samples. Scale bar: 10 μm. <bold>G.</bold>
The LAMP1 distribution studied both in patient tumors (using immunohistochemistry) and cell lines (immunofluorescence). Starting from the left panel, a patient with GIST and excellent response to Glivec; a patient with Merkel cell cancer and known PDGFR activating mutation in its tyrosine kinase domain; the leukemia cell line MV‑4‑11 with a FLT activating mutation; bladder cell line J82 with FGFR activating mutations; and NSCLC cell line NCI-H1781 with a Her2 mutation. The arrows in immunohistochemistry and immunofluorescence images demonstrate diffused LAMP1 distribution. Scale bar: 10 μm. <bold>H.</bold>
Western blot analysis comparing the expression of LAMP1 in multiple cell lines with receptor tyrosine kinase mutations (J82, MV4-11, MOLM-14, and PC9 cells) and WT receptor tyrosine kinases (H1299 and A431 cells). β‑Actin was the loading control.</p>
</caption>
<graphic xlink:href="thnov10p2727g004"></graphic>
</fig>
<fig id="F5" position="float"><label>Figure 5</label>
<caption><p><bold> Targeting the lysosomal pathway may sensitize resistant tumors to EGFR tyrosine kinase inhibitors. A.</bold>
Acridine orange staining and immunofluorescence analysis of LAMP1, pY1068-EGFR, and total EGFR in H1299 cells (EGFR WT cell line resistant to TKIs) treated with chloroquine or vehicle for four hours. DAPI stains thenucleus (green). The percentage of LAMP1 staining per nucleus in CQ treated cells with respect to the control cells is shown in the bar graph. <bold>B.</bold>
Expression of LAMP1 and LC3 in chloroquine-treated H1299. H1299 was treated with increasing concentrations of chloroquine for four hours (10μm and 20μm) (left panels), and for an increasing duration with 10μm of chloroquine (middle panels). The right panel shows corresponding to an increased total LAMP1 and an increased amount of phosphorylated and total EGFR in cells treated with 15μM chloroquine. <bold>C.</bold>
The cell viability assay of inhibitors when used alone and when used in combination with erlotinib are shown. The inhibitors used are erlotinib (2μM), 17-AAG (0.025μM), Monensin (0.02μM), and Chloroquine (5μM). The difference in cell viability of each inhibitor used in-combination with erlotinib (2μM) is shown next to the bar chart. Results shown here are representative of three independent experiments, and error bars represent standard deviations from the mean. <bold>D.</bold>
Western blot of the downstream signaling events after drug treatment with EGFR TKI (Erlotinib), 17-AAG (AAG), or Monensin (Mon) on H1299 cells. Phospho-AKT (pAKT), total AKT, phospho-ERK (pERK), and total ERK were assessed at 8 hours after H1299 cells were treated with either 2μM of Erlotinib (TKI), 17-AAG (0.005μM), or Monensin (0.005μM), or a combination of Erlotinib and 17-AAG (TKI+AAG) or Erlotinib and monensin (TKI+Mon), respectively. <bold>E.</bold>
Cell viability analysis of erlotinib treatment on EGFR wild type cells (H1299) with either control siRNA or SNX1 siRNA (left panel), and PC9 cells transfected with either control or SNX1 plasmids (right panel). SNX1 knockdown cells were treated with increasing concentrations of erlotinib from 0 to 20 μM for 72 hours, and the fold change of surviving cells with respect to untreated cells in each set of experiments is shown. Each data point represents an average of three independent sets of experiments, and errors bars show the standard deviation from the mean. The respective two-tailed p-values at each concentration of erlotinib (2 μM, 5 μM, 10 μM, 15 μM, and 20 μM) are 0.333464, 0.078570, 0.009807, 0.010858, and 0.007565, respectively. PC9 cells were transfected with either control or SNX1 for 48 hours, and their sensitivity to erlotinib determined. Transfected cells were treated with increasing concentrations of erlotinib from 0 to 2 μM for 72 hours, and the percentage of surviving cells with respect to untreated cells in each set of experiments is shown in the chart. Each data point represents an average of three independent sets of identical experiments, and errors bars show the standard deviation from the mean. The respective two-tailed p-values at each concentration of erlotinib (0.0002 μM, 0.002 μM, 0.02 μM, 0.2 μM, and 2 μM) are 0.949983, 0.480825, 0.001439, 0.001235, and 0.001518, respectively). * indicates <italic>p</italic>
-value <0.05.</p>
</caption>
<graphic xlink:href="thnov10p2727g005"></graphic>
</fig>
<fig id="F6" position="float"><label>Figure 6</label>
<caption><p><bold> Targeting the lysosomes or microtubules sensitizes mice with resistance to EGFR TKIs. A.</bold>
EGFR TKI resistant H1975 cells were treated with erlotinib, paclitaxel, hydroxychloroquine (HCQ), a combination of erlotinib with HCQ, and a combination of paclitaxel with hydroxychloroquine (HCQ). Cell lysates were harvested and immunoblotted for pY1068 (pEGFR), EGFR, pAKT, AKT, and β-Actin (loading control). <bold>B.</bold>
The overall treatment plan for the transgenic mice with Doxycycline induced expression of human EGFR with a primary mutation (L858R) and secondary resistance mutation (T790M) (Tet-op-hEGFR-L858R-T790M). <bold>C.</bold>
Graph shows percentage of change in tumor volume between vehicle (n = 6), Gefitnib (n=4), Hydroxychloroquine (HCQ) (n=6), and combination of Gefitnib and HCQ (n = 5) (left). Graph showing percentage of change in tumor volume between vehicle (n = 6), Paclitaxel (n=4), Hydroxychloroquine (HCQ) (n=6) and combination of Paclitaxel and HCQ (n = 6) (right). Significance in differences in tumor volumes with respect to vehicle treatment was determined by t‐test. Error bars denote SEM. ** and *** represent <italic>p</italic>
-values <0.01 and <0.001, respectively. <bold>D.</bold>
Immunohistochemistry analysis of Ki67 using tumors from above mentioned experiment for determination of cell proliferation in tumors. <bold>E.</bold>
Graph showing the percentage of Ki67 staining with respect to the total nuclei from the immunohistochemical analysis of Ki67 from the panel D. Error bars denote S.D, ** represent <italic>p</italic>
-value <0.01. Scale bar: 25 mm.</p>
</caption>
<graphic xlink:href="thnov10p2727g006"></graphic>
</fig>
</floats-group>
</pmc>
<affiliations><list><country><li>Italie</li>
<li>Singapour</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Massachusetts</li>
<li>Toscane</li>
</region>
<settlement><li>Pise</li>
</settlement>
<orgName><li>Université nationale de Singapour</li>
</orgName>
</list>
<tree><noCountry><name sortKey="Hong, Wanjin" sort="Hong, Wanjin" uniqKey="Hong W" first="Wanjin" last="Hong">Wanjin Hong</name>
<name sortKey="Ong, Yan Shan" sort="Ong, Yan Shan" uniqKey="Ong Y" first="Yan Shan" last="Ong">Yan Shan Ong</name>
<name sortKey="Putti, Thomas" sort="Putti, Thomas" uniqKey="Putti T" first="Thomas" last="Putti">Thomas Putti</name>
</noCountry>
<country name="Singapour"><noRegion><name sortKey="Chin, Tan Min" sort="Chin, Tan Min" uniqKey="Chin T" first="Tan-Min" last="Chin">Tan-Min Chin</name>
</noRegion>
<name sortKey="Ali, Azhar" sort="Ali, Azhar" uniqKey="Ali A" first="Azhar" last="Ali">Azhar Ali</name>
<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>
<name sortKey="Goh, Boon Cher" sort="Goh, Boon Cher" uniqKey="Goh B" first="Boon-Cher" last="Goh">Boon-Cher Goh</name>
<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>
<name sortKey="Tenen, Daniel G" sort="Tenen, Daniel G" uniqKey="Tenen D" first="Daniel G." last="Tenen">Daniel G. Tenen</name>
<name sortKey="Wai, Fhu Chee" sort="Wai, Fhu Chee" uniqKey="Wai F" first="Fhu Chee" last="Wai">Fhu Chee Wai</name>
<name sortKey="Wan, Seow Ching" sort="Wan, Seow Ching" uniqKey="Wan S" first="Seow-Ching" last="Wan">Seow-Ching Wan</name>
<name sortKey="Xie, Chen" sort="Xie, Chen" uniqKey="Xie C" first="Chen" last="Xie">Chen Xie</name>
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<country name="États-Unis"><region name="Massachusetts"><name sortKey="Clohessy, John G" sort="Clohessy, John G" uniqKey="Clohessy J" first="John G." last="Clohessy">John G. Clohessy</name>
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<name sortKey="Csizmadia, Eva" sort="Csizmadia, Eva" uniqKey="Csizmadia E" first="Eva" last="Csizmadia">Eva Csizmadia</name>
<name sortKey="Levantini, Elena" sort="Levantini, Elena" uniqKey="Levantini E" first="Elena" last="Levantini">Elena Levantini</name>
<name sortKey="Quinlan, Margaret P" sort="Quinlan, Margaret P" uniqKey="Quinlan M" first="Margaret P" last="Quinlan">Margaret P. Quinlan</name>
<name sortKey="Settleman, Jeff" sort="Settleman, Jeff" uniqKey="Settleman J" first="Jeff" last="Settleman">Jeff Settleman</name>
<name sortKey="Settleman, Jeff" sort="Settleman, Jeff" uniqKey="Settleman J" first="Jeff" last="Settleman">Jeff Settleman</name>
<name sortKey="Tenen, Daniel G" sort="Tenen, Daniel G" uniqKey="Tenen D" first="Daniel G." last="Tenen">Daniel G. Tenen</name>
</country>
<country name="Italie"><region name="Toscane"><name sortKey="Levantini, Elena" sort="Levantini, Elena" uniqKey="Levantini E" first="Elena" last="Levantini">Elena Levantini</name>
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