{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T17:22:26Z","timestamp":1790011346544,"version":"4.0.1"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:00:00Z","timestamp":1727136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cell Biology International"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Crizotinib, as the first\u2010generation of anaplastic lymphoma kinase (ALK) inhibitor, effectively improves the survival time of ALK\u2010positive non\u2010small cell lung cancer (NSCLC) patients. However, its efficacy is severely limited by drug resistance caused by secondary mutations. G1202R and L1196M are classical mutation sites located in ALK kinase domain. They may hinder the binding of ALK inhibitors to the target kinase domain, resulting in drug resistance in patients. However, the exact mechanism of drug resistance mediated by these mutations remains unclear. In this study, we aimed to evaluate how G1202R and L1196M mutations mediate crizotinib resistance. To explore the resistance mechanism, we constructed EML4\u2010ALK G1202R and L1196M mutant cell lines with A549 cells. The results showed that the mutant cells exhibited significant epithelial\u2013mesenchymal transition (EMT) and metastasis compared to control (A549\u2010vector) or wild type (A549\u2010EML4\u2010ALK) cells. Subsequently, it was found that the occurrence of EMT was correlated to the high expression of murine double minute 2 (MDM2) protein and the activation of mitogen\u2010activated protein kinase (MEK)\/extracellular signal\u2010regulated kinase (ERK) pathway in mutant cells. Down\u2010regulation of MDM2 inhibited the activation of MEK\/ERK pathway, thus reversed the EMT process and markedly increased the inhibitory effect of crizotinib on the growth of mutant cells. Collectively, resistance of ALK\u2010positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2\/MEK\/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy.<\/jats:p>","DOI":"10.1002\/cbin.12249","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T00:43:57Z","timestamp":1727225037000},"page":"55-67","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["EML4\u2010ALK G1202R and EML4\u2010ALK L1196M mutations induce crizotinib resistance in non\u2010small cell lung cancer cells through activating epithelial\u2013mesenchymal transition mediated by MDM2\/MEK\/ERK signal axis"],"prefix":"10.1002","volume":"49","author":[{"given":"Yuying","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacology Shenyang Pharmaceutical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of 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