Hatlen MA, Schmidt-Kittler O, Sherwin CA, et al. - Given the absence of a clinically established oncogenic driver of hepatocellular carcinoma (HCC), and the implication of FGF19 receptor, FGFR4, in hepatocarcinogenesis in preclinical investigations and a clinical benefit and tumor regression seen with fisogatinib (BLU-554; a potent and selective inhibitor of FGFR4) in HCC patients with aberrant FGF19 expression, researchers found mutations in the gatekeeper and hinge-1 residues in the kinase domain of FGFR4 upon disease progression in 2 patients who received treatment with fisogatinib. They also corroborated that these identified mutations mediated resistance in vitro and in vivo. In the presence of these mutations, reduction in HCC xenograft growth was induced by a gatekeeper-agnostic, pan-FGFR inhibitor, showing continued FGF19-FGFR4 pathway dependence. Based on these revelations, FGFR4 was validated as an oncogenic driver.