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• W2482427906 abstract "Abstract Advanced, anaplastic lymphoma kinase (ALK)–positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant. Significance: Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118–33. ©2016 AACR. See related commentary by Qiao and Lovly, p. 1084. This article is highlighted in the In This Issue feature, p. 1069" @default.
• W2482427906 created "2016-08-23" @default.
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• W2482427906 date "2016-10-01" @default.
• W2482427906 modified "2023-10-18" @default.
• W2482427906 title "Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in<i>ALK</i>-Rearranged Lung Cancer" @default.
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• W2482427906 doi "https://doi.org/10.1158/2159-8290.cd-16-0596" @default.
• W2482427906 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5050111" @default.
• W2482427906 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27432227" @default.
• W2482427906 hasPublicationYear "2016" @default.
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