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- W2030099076 abstract "Recent approval to market the RAF kinase inhibitor vemurafenib for treatment of metastatic melanomas positive for the BRAFV600E mutation highlights the clinical importance of MEK/ERK signaling in human cancers. Vemurafenib treatment resulted in objective responses in 52% of BRAFV600E mutation melanoma patients, although a subset of patients (20–30%) were reported to develop cutaneous squamous-cell carcinomas (cSCCs) and/or keratoacanthomas, which are independent of the melanoma and thought to be related to exposure to the RAF inhibitor. While vemurafenib effectively inhibits proliferation of BRAFV600E mutant melanomas, vemurafenib and other selective RAF kinase inhibitors can paradoxically activate the MAPK pathway and stimulate growth of BRAF wild-type cells. One hypothesis to explain the appearance cSCCs is that paradoxical activation of the MAPK pathway by RAF inhibitor treatment, in the presence of pre-existing genetic lesions, such as the loss of a tumor suppressor(s), is sufficient to promote cSCC growth. To investigate this hypothesis, we used a genetic murine model (K14-HPV16) for cSCC, which is driven by basal keratinocyte-specific expression (Keratin 14 promoter) of human papiloma virus (HPV) type 16 genes E6 and E7, inactivating the p53 and pRB tumor suppressor proteins respectively. The frequency of cSCC in K14-HPV16 mice is ∼10–20% by 8 months of age. Consistent with our hypothesis, 60 day exposure to vemurafenib at a clinically relevant dose increased the cSCC incidence to ∼65%. In addition, the incidence and severity of skin lesions was proportional to the dose of vemurafenib. Mice treated with vemurafenib also exhibited RAF activation as measured by increased levels of MAPK pathway transcriptional targets in dermal tissues where lesions most often arise. Together, these results suggest that hyperactivation of the MAPK pathway caused by vemurafenib promotes tumorigenesis of HPV-driven cSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B129." @default.
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- W2030099076 date "2011-11-12" @default.
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- W2030099076 title "Abstract B129: RAF inhibition promotes tumorigenesis in a mouse model of HPV-driven squamous cell carcinoma." @default.
- W2030099076 doi "https://doi.org/10.1158/1535-7163.targ-11-b129" @default.
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