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RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors

The New England Journal of Medicine [NEJM], ISSN: 0028-4793, Vol: 366, Issue: 3, Page: 207-215
2012
  • 945
    Citations
  • 0
    Usage
  • 443
    Captures
  • 1
    Mentions
  • 15
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    945
    • Citation Indexes
      939
    • Clinical Citations
      3
      • PubMed Guidelines
        3
    • Policy Citations
      3
      • Policy Citation
        3
  • Captures
    443
  • Mentions
    1
    • Blog Mentions
      1
      • Blog
        1
  • Social Media
    15
    • Shares, Likes & Comments
      15
      • Facebook
        15

Article Description

Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. 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. 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. 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.) Patients with melanoma who are treated with a BRAF inhibitor have a high incidence of keratoacanthomas. Most of the tumors have oncogenic mutations in HRAS that probably preceded the use of the BRAF inhibitor. In animal models, second tumors are blocked when a MEK inhibitor is added to the BRAF inhibitor. The t→a transversion at position 1799 of BRAF ( BRAF V600E ) is present in approximately 50% of patients with metastatic melanoma. 1, 2 BRAF V600E induces constitutive signaling through the mitogen-activated protein kinase (MAPK) pathway, stimulating cancer-cell proliferation and survival. 2 The clinical development of inhibitors of oncogenic BRAF, termed type I BRAF inhibitors, which block the active conformation of the BRAF kinase, has led to a high rate of objective tumor responses and improvement in overall survival, as compared with standard chemotherapy. 3–5 However, nonmelanoma skin cancers — well-differentiated cutaneous squamous-cell carcinomas and keratoacanthomas — have developed in approximately 15. . .

Bibliographic Details

Su, Fei; Viros, Amaya; Milagre, Carla; Trunzer, Kerstin; Bollag, Gideon; Spleiss, Olivia; Reis-Filho, Jorge S; Kong, Xiangju; Koya, Richard C; Flaherty, Keith T; Chapman, Paul B; Kim, Min Jung; Hayward, Robert; Martin, Matthew; Yang, Hong; Wang, Qiongqing; Hilton, Holly; Hang, Julie S; Noe, Johannes; Lambros, Maryou; Geyer, Felipe; Dhomen, Nathalie; Niculescu-Duvaz, Ion; Zambon, Alfonso; Niculescu-Duvaz, Dan; Preece, Natasha; Robert, Lídia; Otte, Nicholas J; Mok, Stephen; Kee, Damien; Ma, Yan; Zhang, Chao; Habets, Gaston; Burton, Elizabeth A; Wong, Bernice; Nguyen, Hoa; Kockx, Mark; Andries, Luc; Lestini, Brian; Nolop, Keith B; Lee, Richard J; Joe, Andrew K; Troy, James L; Gonzalez, Rene; Hutson, Thomas E; Puzanov, Igor; Chmielowski, Bartosz; Springer, Caroline J; McArthur, Grant A; Sosman, Jeffrey A; Lo, Roger S; Ribas, Antoni; Marais, Richard

Faculty Opinions Ltd

Medicine

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