Inhibition of Fibroblast Growth Factor Receptor Attenuates Ultraviolet B-Induced Skin Carcinogenesis.

Altered FGFR signaling has been shown to play a role in a number of cancers. However, the role of FGFR signaling in the development and progression of ultraviolet B-induced (UVB) induced cutaneous squamous cell carcinoma (cSCC) remains unclear. In the current study, the effect of UVB radiation on FGFR activation and its downstream signaling in mouse skin epidermis was examined. In addition, the impact of FGFR inhibition on UVB-induced signaling and skin carcinogenesis was also investigated. Exposure of mouse dorsal skin to UVB significantly increased phosphorylation of FGFRs in the epidermis as well as activation of downstream signaling pathways, including AKT/mTOR, STATs and MAPK. Topical application of the pan-FGFR inhibitor AZD4547 to mouse skin prior to exposure to UVB significantly inhibited FGFR phosphorylation as well as mTORC1, STAT3 and MAPK activation (i.e., phosphorylation). Moreover, AZD4547 pretreatment significantly inhibited UVB-induced epidermal hyperplasia and hyperproliferation and reduced infiltration of mast cells and macrophages into the dermis. AZD4547 treatment also significantly inhibited mRNA expression of inflammatory genes in the epidermis. Finally, mice treated topically with AZD4547 prior to UVB exposure showed decreased cSCC incidence and increased survival rate. Collectively, the current data supports the hypothesis that inhibition of FGFR in epidermis may provide a new strategy to prevent and/or treat UVB-induced cSCC.