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For the treatment of patients with ALK\u2010rearranged NSCLC, various additional ALK\u2010TKIs have been developed. Ceritinib is a second\u2010generation ALK\u2010TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first\u2010generation ALK\u2010TKI)\u2010refractory ALK\u2010rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib\u2010resistant, echinoderm microtubule\u2010associated protein\u2010like 4 (EML4)\u2010ALK\u2013positive H3122 cells and ceritinib\u2010resistant patient\u2010derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib\u2010resistant patient\u2010derived specimens confirmed that tyrosine\u2010protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and\/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms.<\/jats:p>","DOI":"10.1111\/cas.15529","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T13:23:46Z","timestamp":1660224226000},"page":"3888-3900","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Fibroblast growth factor receptor 3 overexpression mediates <scp>ALK<\/scp> inhibitor resistance in <scp>ALK<\/scp>\u2010rearranged non\u2013small cell lung cancer"],"prefix":"10.1111","volume":"113","author":[{"given":"Takuya","family":"Sakashita","sequence":"first","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center Japanese Foundation for Cancer Research  Tokyo Japan"},{"name":"Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences The University of 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