Abstract
Abstract A subset of melanoma patients (18-30%) treated with Vemurafenib (and other RAF inhibitors) develop spontaneous cutaneous squamous-cell carcinoma (cSCC) and/or keratoacanthoma (KA). Preclinical studies demonstrate that RAF inhibitors paradoxically activate the MAPK pathway and stimulate growth of RAS mutated cells. Based on these observations it has been proposed that drug induced MAPK activation in pre-cancerous tissues may account for the high incidence of cSCC and KA in treated patients. Because human cSCC is frequently positive for human papillomavirus (HPV) DNA, we hypothesized that RAF inhibitors promote tumorigenesis in HPV infected epidermis. To investigate this possibility, we used a transgenic murine model (K14-HPV16) of cSCC, driven by basal keratinocyte-specific expression (K14 promoter) of HPV type 16 early genes including E6 and E7, which inactivates p53 and pRB tumor suppressors. Exposure to Vemurafenib elevated MAPK markers in epidermis and increased cSCC incidence from 22% to 70%. Exome sequencing revealed that 100% of cSCCs from untreated mice harbored activating RAS mutations, yet 55% of cSCCs from Vemurafenib treated mice were RAS wild-type. Concomitant treatment with a MEK inhibitor reduced cSCC frequency, and MEK inhibitor alone was sufficient to completely regress established cSCCs. Together, these results suggest that cSCC is dependent upon MAPK activation induced either by a RAS oncogene or alternatively by exposure to RAF inhibitors in HPV infected keratinocytes. Citation Format: Matthew Holderfield, Edward Lorenzana, Ben Weisburd, Lisa Lomovasky, Majid Ghoddusi, Dylan Daniel, Nancy Pryer, Frank McCormick, Darrin Stuart. Vemurafenib promotes RAS wild-type tumor formation in a mouse model of HPV-driven cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-61. doi:10.1158/1538-7445.AM2013-LB-61
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
