期刊
CLINICAL CANCER RESEARCH
卷 20, 期 5, 页码 1204-1211出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-1733
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资金
- NCI [R01 CA140594, NCI-CA122794, NCI-CA166480, NCI-CA163896, NCI-P01CA154303, NCI-P01CA120964, R01CA136851]
- Uniting Against Lung Cancer Foundation
- Bonnie J. Addario Lung Cancer Foundation
- Claudia Barr Award in Basic Cancer Research
Purpose: To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion. Experimental Design: We conducted a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib the standard-of-care cytotoxic agents docetaxel or pemetrexed. Results: Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared with chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared with chemotherapy-treated mice. Pemetrexed produced superior overall survival compared with docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. In addition, in the EML4-ALK-driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1 174L. Conclusions: Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor-naive disease and support further clinical investigation of HSP90 inhibitors and second-generation ALK inhibitors in tumors with primary or acquired crizotinib resistance. (C) 2013 AACR.
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