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.).
authors.affiliation: Hoffmann-La Roche, Nutley, NJ, USA.
authors.forename: Fei
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authors.lastname: Su
authors.forename: Amaya
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authors.lastname: Viros
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authors.lastname: Milagre
authors.forename: Kerstin
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authors.lastname: Trunzer
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authors.lastname: Niculescu-Duvaz
authors.forename: Alfonso
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authors.forename: Lídia
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authors.forename: Chao
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authors.lastname: Habets
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Burton
authors.forename: Bernice
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authors.lastname: Wong
authors.forename: Hoa
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authors.lastname: Nguyen
authors.forename: Mark
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authors.lastname: Kockx
authors.forename: Luc
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authors.lastname: Andries
authors.forename: Brian
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authors.lastname: Lestini
authors.forename: Keith B
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authors.lastname: Nolop
authors.forename: Richard J
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authors.forename: Andrew K
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authors.lastname: Joe
authors.forename: James L
authors.initials: JL
authors.lastname: Troy
authors.forename: Rene
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authors.lastname: Gonzalez
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.forename: Antoni
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authors.lastname: Ribas
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mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases