FGFR2 fusion protein-driven mouse models of intrahepatic cholangiocarcinoma unveil a necessary role for Erk signalling

摘要: Abstract Background and aims About 15% of intrahepatic cholangiocarcinoma (iCCA) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), most often in concert with mutationally inactivated TP53, CDKN2A or BAP1. FFs span residues 1-768 FGFR2 fused to sequences encoded by any a long list (>60) partner genes, configuration sufficient ignite oncogenic FF activation. In line, FGFR-specific tyrosine kinase inhibitors (F-TKI) were shown provide clinical benefit FF+ iCCA, although responses partial and/or limited resistance mechanisms, including the V565F gatekeeper mutation. Herein we present an FF-driven murine iCCA model exploit its potential for pre-clinical studies on therapeutic targeting. Methods Four carrying different expressed Tp53-/- mouse liver organoids. Tumorigenic properties genetically modified organoids assessed intrahepatic/subcutaneous transplantation immuno-deficient mice. Cellular models derived from neoplastic lesions exploited studies. Results Tumors diagnosed as CCA obtained upon FF-expressing The penetrance this tumorigenic phenotype was influenced identity. Tumor 2D cell lines addicted signaling via Ras-Erk, regardless identity presence Double blockade FF-Ras-Erk pathway concomitant pharmacological inhibition Mek1/2 provided greater efficacy than single agent F-TKI vitro vivo. Conclusions pathogenesis successfully modelled background. This revealed biological heterogeneity among structurally FFs. FF-Erk deserves consideration improving precision-based approaches against human iCCA.