Vemurafenib cooperates with HPV to promote initiation of cutaneous tumors
Menée à l'aide d'un modèle murin transgénique, cette étude met en évidence des mécanismes par lesquels le vemurafenib favorise la formation d'un carcinome épidermoïde cutané dans les tissus infectés par le papillomavirus humain
Treatment with RAF inhibitors such as vemurafenib cause the development of cutaneous squamous cell carcinomas (cSCC) or keratoacanthomas (KA) as a side-effect in 18-30% of patients. It is known that RAF inhibitors activate the MAPK pathway and stimulate growth of RAS mutated cells, possibly accounting for up to 60% of cSCC or KA 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 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.
Cancer Research 2014