title: Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1.
abstract: OBJECTIVE
  The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib.
  
  
  METHODS
  Thirty-one skin lesions from patients receiving sorafenib were characterized clinically and pathologically. DNA extracted from the lesions was screened for mutation hot spots of HRAS, NRAS, KiRAS, TP53, EGFR, BRAF, AKT1, PI3KCA, TGFBR1, and PTEN. Biological effect of sorafenib was studied in vivo in normal skin specimen and in vitro on cultured keratinocytes.
  
  
  RESULTS
  We observed a continuous spectrum of lesions: from benign to more inflammatory and proliferative lesions, all seemingly initiated in the hair follicles. Eight oncogenic HRAS, TGFBR1, and TP53 mutations were found in 2 benign lesions, 3 keratoacanthomas (KA) and 3 KA-like squamous cell carcinoma (SCC). Six of them correspond to the typical UV signature. Treatment with sorafenib led to an increased keratinocyte proliferation and a tendency toward increased mitogen-activated protein kinase (MAPK) pathway activation in normal skin. Sorafenib induced BRAF-CRAF dimerization in cultured keratinocytes and activated CRAF with a dose-dependent effect on MAP-kinase pathway activation and on keratinocyte proliferation.
  
  
  CONCLUSIONS
  Sorafenib induces keratinocyte proliferation in vivo and a time- and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors.
authors.affiliation: Department of Medical Oncology and Pathology, Institute Gustave Roussy, Villejuif, France.
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Arnault
authors.forename: Christine
authors.initials: C
authors.lastname: Mateus
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Gorana
authors.initials: G
authors.lastname: Tomasic
authors.forename: Janine
authors.initials: J
authors.lastname: Wechsler
authors.forename: Emilie
authors.initials: E
authors.lastname: Hollville
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: David
authors.initials: D
authors.lastname: Malka
authors.forename: Alain
authors.initials: A
authors.lastname: Sarasin
authors.forename: Magalie
authors.initials: M
authors.lastname: Larcher
authors.forename: Jocelyne
authors.initials: J
authors.lastname: André
authors.forename: Nyam
authors.initials: N
authors.lastname: Kamsu-Kom
authors.forename: Lise
authors.initials: L
authors.lastname: Boussemart
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Alain
authors.initials: A
authors.lastname: Spatz
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: Sabine
authors.initials: S
authors.lastname: Druillennec
authors.forename: Stephan
authors.initials: S
authors.lastname: Vagner
authors.forename: Alain
authors.initials: A
authors.lastname: Eychène
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dumaz
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects; D001557:Benzenesulfonates / Q000009:adverse effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011725:Pyridines / Q000009:adverse effects*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics*; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects; D048490:raf Kinases / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D000077157:Sorafenib; D017346:Protein Serine-Threonine Kinases; D048490:raf Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins