title: RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors.
abstract: OBJECTIVE
  RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation.
  
  
  METHODS
  Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform.
  
  
  RESULTS
  Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1%; immunosuppression, 18.9%; and spontaneous, 17.6%; P = not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type.
  
  
  CONCLUSIONS
  Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.
authors: Broad Institute of Massachusetts Institute of Technology, Cambridge, USA.
authors: Patrick A
authors: PA
authors: Oberholzer
authors: Damien
authors: D
authors: Kee
authors: Piotr
authors: P
authors: Dziunycz
authors: Antje
authors: A
authors: Sucker
authors: Nyam
authors: N
authors: Kamsukom
authors: Robert
authors: R
authors: Jones
authors: Christine
authors: C
authors: Roden
authors: Clinton J
authors: CJ
authors: Chalk
authors: Kristin
authors: K
authors: Ardlie
authors: Emanuele
authors: E
authors: Palescandolo
authors: Adriano
authors: A
authors: Piris
authors: Laura E
authors: LE
authors: MacConaill
authors: Caroline
authors: C
authors: Robert
authors: Günther F L
authors: GF
authors: Hofbauer
authors: Grant A
authors: GA
authors: McArthur
authors: Dirk
authors: D
authors: Schadendorf
authors: Levi A
authors: LA
authors: Garraway
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001557:Benzenesulfonates / Q000009:adverse effects / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000077157:Sorafenib; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013449:Sulfonamides; D000077484:Vemurafenib; D009536:Niacinamide; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases