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We urgently need to understand the underlying molecular mechanism of drug resistance to study the therapeutic targets of mutant drug\u2010resistant NSCLC cells. The silent information regulator sirtuin1 (SIRT1) can regulate the normal energy metabolism of cells, but its role in cancer is still unclear. In our report, it was found that the SIRT1 in EML4\u2010ALK G1202R and EML4\u2010ALK L1196M mutant drug\u2010resistant cells was downregulated compared with EML4\u2010ALK NSCLC cells. The high expression of SIRT1 was related to the longer survival time of patients with lung cancer. Activation of SIRT1 induced autophagy and suppressed the invasion and migration of mutant cells. Further experiments indicated that the activation of SIRT1 inhibited the phosphorylation level of mTOR and S6K by upregulating the expression of AMPK, thus activating autophagy. SIRT1 can significantly enhanced the sensitivity of mutant cells to crizotinib, improved its ability to promote apoptosis of mutant cells, and inhibited cell proliferation. In conclusion, SIRT1 is a key regulator of drug resistant in EML4\u2010ALK L1196M and G1202R mutant cells. SIRT1 may be a novel therapeutic target for EML4\u2010ALK drug resistant NSCLC.<\/jats:p>","DOI":"10.1002\/mc.23799","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T13:46:25Z","timestamp":1722347185000},"page":"2133-2144","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["SIRT1 silencing promotes EMT and Crizotinib resistance by regulating autophagy through AMPK\/mTOR\/S6K signaling pathway in EML4\u2010ALK L1196M and EML4\u2010ALK G1202R mutant non\u2010small cell lung cancer cells"],"prefix":"10.1002","volume":"63","author":[{"given":"Qian","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacology Shenyang Pharmaceutical University Shenyang Shenhe District China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Shenyang Pharmaceutical 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