title: Vemurafenib cooperates with HPV to promote initiation of cutaneous tumors.
abstract: Treatment with RAF inhibitors such as vemurafenib causes the development of cutaneous squamous cell carcinomas (cSCC) or keratoacanthomas as a side effect in 18% to 30% of patients. It is known that RAF inhibitors activate the mitogen-activated protein kinase (MAPK) pathway and stimulate growth of RAS-mutated cells, possibly accounting for up to 60% of cSCC or keratoacanthoma lesions with RAS mutations, but other contributing events are obscure. To identify such events, we evaluated tumors from patients treated with vemurafenib for the presence of human papilloma virus (HPV) DNA and identified 13% to be positive. Using a transgenic murine model of HPV-driven cSCC (K14-HPV16 mice), we conducted a functional test to determine whether administration of RAF inhibitors could promote cSCC in HPV-infected tissues. Vemurafenib treatment elevated MAPK markers and increased cSCC incidence from 22% to 70% in this model. Furthermore, 55% of the cSCCs arising in vemurafenib-treated mice exhibited a wild-type Ras genotype, consistent with the frequency observed in human patients. Our results argue that HPV cooperates with vemurafenib to promote tumorigenesis, in either the presence or absence of RAS mutations.
authors: Authors' Affiliations: Novartis Institutes for Biomedical Research, Emeryville; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California; Dermatology Unit and INSERM U 981; Department of Medical Biology and Pathology; Laboratory and Biobank; INSERM U 981, Institut Gustave Roussy, Villejuif Paris-Sud; and Unité de Génétique, Papillomavirus et Cancer Humain, Institut Pasteur, Paris, France.
authors: Matthew
authors: M
authors: Holderfield
authors: Edward
authors: E
authors: Lorenzana
authors: Ben
authors: B
authors: Weisburd
authors: Lisa
authors: L
authors: Lomovasky
authors: Lise
authors: L
authors: Boussemart
authors: Ludovic
authors: L
authors: Lacroix
authors: Gorana
authors: G
authors: Tomasic
authors: Michel
authors: M
authors: Favre
authors: Stephan
authors: S
authors: Vagner
authors: Caroline
authors: C
authors: Robert
authors: Majid
authors: M
authors: Ghoddusi
authors: Dylan
authors: D
authors: Daniel
authors: Nancy
authors: N
authors: Pryer
authors: Frank
authors: F
authors: McCormick
authors: Darrin
authors: D
authors: Stuart
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D055088:Early Detection of Cancer; D005838:Genotype; D052162:Human papillomavirus 16 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects*; D053547:Keratin-14 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology / Q000821:virology; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D053547:Keratin-14; C507446:Krt14 protein, mouse; D013449:Sulfonamides; D000077484:Vemurafenib