DARK AND BRIGHT SIDE OF TARGETING THE FIBROBLAST GROWTH FACTOR RECEPTOR 4 IN THE LIVER

The Fibroblast growth factor (FGF) receptor 4 (FGFR4) and its cognate ligand, FGF19 are implicated in an ample range of cellular processes, including differentiation, metabolism and proliferation. Their aberrant activation has been associated to the development of hepatic tumours, acting as an oncogenic pathway. Despite the great advances in early diagnosis, and the development of new therapies, liver cancer still presents with a high mortality due to two main culprits: high molecular heterogeneity and unclear molecular targeting. The development of FGFR4 inhibitors is a promising tool in patients with concomitant supraphysiological levels of FGF19 and several clinical trials are ongoing for the treatment of patients with advanced hepatocellular carcinoma (HCC). Conversely, FGFR4-KLOTHO β activation via the use of newly generated FGF19 analogues represent a novel therapeutic strategy in patients presenting with cholestatic liver disorders and NASH and, therefore, could prevent the development of metabolic HCC. Here, we provide an updated overview of the currently available therapeutic options targeting FGFR4 in HCC and other liver diseases, highlighting the need of carefully stratifying patients' groups and personalising therapeutic strategies.