RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors Journal Article
| Authors: | Su, F.; Viros, A.; Milagre, C.; Trunzer, K.; Bollag, G.; Spleiss, O.; Reis-Filho, J. S.; Kong, X.; Koya, R. C.; Flaherty, K. T.; Chapman, P. B.; Kim, M. J.; Hayward, R.; Martin, M.; Yang, H.; Wang, Q.; Hilton, H.; Hang, J. S.; Noe, J.; Lambros, M.; Geyer, F.; Dhomen, N.; Niculescu-Duvaz, I.; Zambon, A.; Niculescu-Duvaz, D.; Preece, N.; Robert, L.; Otte, N. J.; Mok, S.; Kee, D.; Ma, Y.; Zhang, C.; Habets, G.; Burton, E. A.; Wong, B.; Nguyen, H.; Kockx, M.; Andries, L.; Lestini, B.; Nolop, K. B.; Lee, R. J.; Joe, A. K.; Troy, J. L.; Gonzalez, R.; Hutson, T. E.; Puzanov, I.; Chmielowski, B.; Springer, C. J.; McArthur, G. A.; Sosman, J. A.; Lo, R. S.; Ribas, A.; Marais, R. |
| Article Title: | RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors |
| Abstract: | 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.) Copyright © 2012 Massachusetts Medical Society. |
| Keywords: | signal transduction; mitogen activated protein kinase; human tissue; aged; aged, 80 and over; middle aged; unclassified drug; gene mutation; human cell; mutation; squamous cell carcinoma; carcinoma, squamous cell; cancer growth; nonhuman; cell proliferation; animals; mice; melanoma; gene expression; skin neoplasms; transcription initiation; animal experiment; animal model; protein p53; oncogene h ras; skin carcinoma; drug dose escalation; protein kinase inhibitors; gene expression regulation, neoplastic; sulfonamides; ras protein; drug bioavailability; phase 1 clinical trial; cancer tissue; mutation rate; cyclin dependent kinase inhibitor 2a; oncogene k ras; genes, ras; indoles; k ras protein; mitogen activated protein kinase kinase; mitogen-activated protein kinase kinases; proto-oncogene proteins b-raf; cell mutant; drug exposure; skin carcinogenesis; keratoacanthoma; b raf kinase inhibitor; 2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3,4 difluorobenzamide; protein serine threonine kinase inhibitor; oncogene n ras; plx 4720; vemurafenib; px 4720 |
| Journal Title: | New England Journal of Medicine |
| Volume: | 366 |
| Issue: | 3 |
| ISSN: | 0028-4793 |
| Publisher: | Massachusetts Medical Society |
| Date Published: | 2012-01-19 |
| Start Page: | 207 |
| End Page: | 215 |
| Language: | English |
| DOI: | 10.1056/NEJMoa1105358 |
| PROVIDER: | scopus |
| PUBMED: | 22256804 |
| PMCID: | PMC3724537 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 1 March 2012" - "CODEN: NEJMA" - "Source: Scopus" |
