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However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK\u2010positive lung cancer during multiple ALK\u2010TKI treatments to reveal the resistance mechanisms to ALK\u2010TKI. Among 32 patients, 24\u00a0patients received more than two ALK\u2010TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P\u2010gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M\u00a0+\u00a0G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK\u2010TKI treatment duration was longer in the on\u2010target treatment group than that in the off\u2010target group (13.0 vs 1.2\u00a0months). In conclusion, resistance to ALK\u2010TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK\u2010TKI treatment strategies.<\/jats:p>","DOI":"10.1111\/cas.14314","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T08:50:27Z","timestamp":1579596627000},"page":"932-939","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Drug resistance mechanisms in Japanese anaplastic lymphoma kinase\u2010positive non\u2013small cell lung cancer and the clinical responses based on the resistant mechanisms"],"prefix":"10.1111","volume":"111","author":[{"given":"Noriko","family":"Yanagitani","sequence":"first","affiliation":[{"name":"Department of Thoracic Medical Oncology The Cancer Institute Hospital Japanese Foundation for Cancer Research Tokyo 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