RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors
Menée sur 21 échantillons tumoraux prélevés sur des patients traités à l'aide de vemurafenib, un inhibiteur de BRAF, cette étude montre que des mutations du gène RAS sont fréquentes dans les carcinomes épidermoïdes cutanés et les kératoacanthomes qui se développent chez ces patients
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.)
Supported in part by Hoffmann–La Roche and Plexxikon (to Drs. Su, Trunzer, and Bollag); the Seaver Institute, the Louise Belley and Richard Schnarr Fund, the Fred L. Hartley Family Foundation, the Wesley Coyle Memorial Fund, the Ruby Family Foundation, the Albert Stroberg and Betsy Patterson Fund, the Jonsson Cancer Center Foundation, and the Caltech–UCLA Joint Center for Translational Medicine (to Drs. Lo and Ribas); the European Organisation for Research and Treatment of Cancer Melanoma Group, Cancer Research U.K. (CRUK) (C107/A10433 and CRUK-A8274), the American Institute for Cancer Research (09-0773), and the Institute of Cancer Research (to Dr. Marais); and Breakthrough Breast Cancer and the 2010 CRUK Future Leaders Prize in Cancer Research (to Dr. Reis-Filho).
New England Journal of Medicine , résumé, 2011