We not only demonstrate the clinical relevance of these patient-derived FGFR2 fusion-positive ICC models by testing standard-of-care therapeutic strategies, but we also utilized these resources to identify and validate the synergistic effect of FGFR2 inhibition together with pan-histone deacetylase (HDAC) inhibition, a strategy that warrants further exploration in a clinical trial. Here, HDAC9 is linked to intrahepatic cholangiocarcinoma.