Abstract
The development of keratinocytic skin tumors, presumably attributable to paradoxical activation of the MAPK pathway, represents a relevant side effect of targeted therapies with BRAF inhibitors (BRAFis). The role of cutaneous papillomavirus infection in BRAFi-associated skin carcinogenesis, however, is still inconclusive. Employing the Mus musculus papillomavirus 1 (MmuPV1) skin infection model, the impact of BRAFis and UVB exposure on papillomavirus induced skin tumorigenesis was investigated in immunocompetent FVB/NCrl mice. Systemic BRAF inhibition in combination with UVB light induced skin tumors in 62% of the MmuPV1-infected animals. In contrast, significantly fewer tumors were observed in the absence of either BRAF inhibition, UVB irradiation or virus infection, as demonstrated by lesional outgrowth in 20%, 5% and 0% of the mice, respectively. Combinatory exposure to BRAFis and UVB favored productive viral infection, which was shown by high numbers of MmuPV1 genome copies and E1^E4 spliced transcripts and an abundance of E6/E7 oncogene mRNA and viral capsid proteins. BRAF inhibition, but not viral infection or UVB light, activated ERK1/2, whereas γH2AX expression, inducible by UVB light, remained unaltered by BRAFis. These results provide experimental evidence that BRAF inhibition and UVB irradiation synergistically promote MmuPV1-induced skin tumor development in vivo. This indicates an alternative pathway by which papillomavirus skin infection may contribute to BRAFi-associated skin tumorigenesis.