Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors
Identifieur interne : 000035 ( Main/Exploration ); précédent : 000034; suivant : 000036Targeting 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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Le document en format XML
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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>
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</TEI>
<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>
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<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>
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<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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<name sortKey="Xie, Chen" sort="Xie, Chen" uniqKey="Xie C" first="Chen" last="Xie">Chen Xie</name>
</country>
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<name sortKey="Levantini, Elena" sort="Levantini, Elena" uniqKey="Levantini E" first="Elena" last="Levantini">Elena Levantini</name>
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<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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