期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 366, 期 3, 页码 207-215出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1105358
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资金
- Hoffmann-La Roche
- Plexxikon
- Seaver Institute
- Louise Belley and Richard Schnarr Fund
- Fred L. Hartley Family Foundation
- Wesley Coyle Memorial Fund
- Ruby Family Foundation
- Albert Stroberg and Betsy Patterson Fund
- Jonsson Cancer Center Foundation
- Caltech-UCLA Joint Center for Translational Medicine
- European Organisation for Research and Treatment of Cancer Melanoma Group, Cancer Research U.K. (CRUK) [C107/A10433, CRUK-A8274]
- American Institute for Cancer Research [09-0773]
- Institute of Cancer Research
- Breakthrough Breast Cancer
- Cancer Research UK [19279, 11566] Funding Source: researchfish
BACKGROUND Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. METHODS We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. RESULTS Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. CONCLUSIONS Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.)
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