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Inhibition of autophagy potentiates the cytotoxicity of the irreversible FGFR1-4 inhibitor FIIN-2 on lung adenocarcinoma.

ABSTRACT: For patients with platinum-resistant lung adenocarcinoma (LUAD), the exploration of new effective drug candidates is urgently needed. Fibroblast growth factor receptors (FGFRs) have been identified as promising targets for LUAD therapy. The purpose of this study was to determine the exact role of the irreversible FGFR1-4 inhibitor FIIN-2 in LUAD and to clarify its underlying molecular mechanisms. Our results demonstrated that FIIN-2 significantly inhibited the proliferation, colony formation, and migration of A549 and A549/DDP cells but induced the mitochondria-mediated apoptosis of these cells. Meanwhile, FIIN-2 increased the autophagy flux of A549 and A549/DDP cells by inhibiting the mammalian target of rapamycin (mTOR) and further activating the class III PI3K complex pathway. More importantly, in vivo and in vitro experiments showed that autophagy inhibitors could enhance the cytotoxicity of FIIN-2 on A549 and A549/DDP cells, confirming that FIIN-2 induced protective autophagy. These findings indicated that FIIN-2 is a potential drug candidate for LUAD treatment, and its use in combination with autophagy inhibitors might be an efficient treatment strategy, especially for patients with cisplatin resistance.

SUBMITTER: Jia X

PROVIDER: S-EPMC9428205 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Inhibition of autophagy potentiates the cytotoxicity of the irreversible FGFR1-4 inhibitor FIIN-2 on lung adenocarcinoma.

Jia Xiuqin X Xin Ming M Xu Juanjuan J Xiang Xindong X Li Xuan X Jiao Yuhan Y Wang Lulin L Jiang Jingjing J Pang Feng F Zhang Xianzhen X Zhang Jian J

Cell death & disease 20220830 8

For patients with platinum-resistant lung adenocarcinoma (LUAD), the exploration of new effective drug candidates is urgently needed. Fibroblast growth factor receptors (FGFRs) have been identified as promising targets for LUAD therapy. The purpose of this study was to determine the exact role of the irreversible FGFR1-4 inhibitor FIIN-2 in LUAD and to clarify its underlying molecular mechanisms. Our results demonstrated that FIIN-2 significantly inhibited the proliferation, colony formation, an ...[more]

PMID: 36042213

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Project description:IntroductionEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied.ResultsForty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2.MethodsAfatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method.ConclusionsT790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TKI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.

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Inhibition of autophagy potentiates the cytotoxicity of the irreversible FGFR1-4 inhibitor FIIN-2 on lung adenocarcinoma.

Publications

Inhibition of autophagy potentiates the cytotoxicity of the irreversible FGFR1-4 inhibitor FIIN-2 on lung adenocarcinoma.

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