EGFR TKIs impair lysosome-dependent degradation of SQSTM1 to compromise the effectiveness in lung cancer
Identifieur interne : 000866 ( Main/Exploration ); précédent : 000865; suivant : 000867EGFR TKIs impair lysosome-dependent degradation of SQSTM1 to compromise the effectiveness in lung cancer
Auteurs : Lixian Yang [République populaire de Chine] ; Shilong Ying [République populaire de Chine] ; Shiman Hu [République populaire de Chine] ; Xiangtong Zhao [République populaire de Chine] ; Muchun Li [République populaire de Chine] ; Miaoqin Chen [République populaire de Chine] ; Yiran Zhu [République populaire de Chine] ; Ping Song [République populaire de Chine] ; Liyuan Zhu [République populaire de Chine] ; Tingting Jiang [République populaire de Chine] ; Huimin An [République populaire de Chine] ; Neelum Aziz Yousafzai [République populaire de Chine] ; Wenxia Xu [République populaire de Chine] ; Zhiguo Zhang [République populaire de Chine] ; Xian Wang [République populaire de Chine] ; Lifeng Feng [République populaire de Chine] ; Hongchuan Jin [République populaire de Chine]Source :
- Signal Transduction and Targeted Therapy [ 2095-9907 ] ; 2019.
Abstract
Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in
Url:
DOI: 10.1038/s41392-019-0059-4
PubMed: 31637005
PubMed Central: 6799834
Affiliations:
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Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Hu, Shiman" sort="Hu, Shiman" uniqKey="Hu S" first="Shiman" last="Hu">Shiman Hu</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Zhao, Xiangtong" sort="Zhao, Xiangtong" uniqKey="Zhao X" first="Xiangtong" last="Zhao">Xiangtong Zhao</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id 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xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Xu, Wenxia" sort="Xu, Wenxia" uniqKey="Xu W" first="Wenxia" last="Xu">Wenxia Xu</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Zhiguo" sort="Zhang, Zhiguo" uniqKey="Zhang Z" first="Zhiguo" last="Zhang">Zhiguo Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering,</institution><institution>Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Xian" sort="Wang, Xian" uniqKey="Wang X" first="Xian" last="Wang">Xian Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Department of Medical Oncology, Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Feng, Lifeng" sort="Feng, Lifeng" uniqKey="Feng L" first="Lifeng" last="Feng">Lifeng Feng</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Jin, Hongchuan" sort="Jin, Hongchuan" uniqKey="Jin H" first="Hongchuan" last="Jin">Hongchuan Jin</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1759 700X</institution-id><institution-id institution-id-type="GRID">grid.13402.34</institution-id><institution>Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital,</institution><institution>Medical School of Zhejiang University,</institution></institution-wrap>Hangzhou, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hangzhou</wicri:regionArea></affiliation></author></analytic><series><title level="j">Signal Transduction and Targeted Therapy</title><idno type="ISSN">2095-9907</idno><idno type="eISSN">2059-3635</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 id="Par1">Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in <italic>EGFR</italic>. However, much less effort has been put into alternative strategies, such as targeting the intrinsic protective responses to EGFR TKIs. In this study, we found that EGFR TKIs, including gefitinib and AZD9291, impaired lysosome-dependent degradation of SQSTM1, thus compromising their anti-cancer efficiency. By accumulating in the lysosome lumen, gefitinib and AZD9291 attenuated lysosomal acidification and impaired autolysosomal degradation of SQSTM1 owing to their intrinsic alkalinity. As a result, SQSTM1 protein was stabilized in response to gefitinib and AZD9291 treatment and conferred EGFR TKI resistance. Depleting SQSTM1 significantly increased the sensitivity of NSCLC cells to gefitinib and AZD9291 both in vitro and in vivo. Furthermore, a chemically modified gefitinib analog lacking alkalinity displayed stronger inhibitory effects on NSCLC cells. Therefore, targeting accumulated SQSTM1 or chemically modified EGFR TKIs may represent new strategies to increase the effectiveness of EGFR targeted therapy.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J Ferlay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pao, W" uniqKey="Pao W">W Pao</name></author><author><name sortKey="Chmielecki, J" uniqKey="Chmielecki J">J Chmielecki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hirsch, Fr" uniqKey="Hirsch F">FR Hirsch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kuwano, M" uniqKey="Kuwano M">M Kuwano</name></author><author><name sortKey="Sonoda, K" uniqKey="Sonoda K">K Sonoda</name></author><author><name sortKey="Murakami, Y" uniqKey="Murakami Y">Y Murakami</name></author><author><name sortKey="Watari, K" uniqKey="Watari K">K 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