457 Impact of MT2 Melatonin Receptor Deletion on Cellular Senescence in Cholangiocytes Isolated from Mice after Cholestatic Liver Injury

BGJ398, a pan-FGFR inhibitor currently being employed in human trials, resulted in a significant increase in cellular apoptosis.Tumor tissue from mice sacrificed 10 weeks after biliary oncogene transduction of AKT and YAP also demonstrated increased expression of FGFR 1-4.BGJ398 treatment resulted in a significant reduction in tumor burden and increase in tumor cell apoptosis as assessed by the TUNEL assay in our mouse model of CCA.In Conclusion, YAP is a critical oncogene in CCA and promotes biliary carcinogenesis, in part, via upregulation of FGFR.In a murine genetic model of CCA, the FGFR specific inhibitor BGJ398 significantly reduces tumor burden by inducing apoptosis.Thus, inhibition of FGFR represents a promising therapeutic approach in YAP-driven human CCA.