期刊
CANCER DISCOVERY
卷 6, 期 10, 页码 1118-1133出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-16-0596
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资金
- NCI [5R01CA164273, C06CA059267]
- National Foundation for Cancer Research
- Be a Piece of the Solution
- Evan Spirito Foundation
- Lung-Strong
- Grants-in-Aid for Scientific Research [16H04715, 15K14412] Funding Source: KAKEN
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, ALK(G1202R), 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. (C) 2016 AACR.
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