title: Targeted inhibition of the FGF19-FGFR4 pathway in hepatocellular carcinoma; translational safety considerations.
abstract: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death and new therapies are urgently required to treat this disease. Recent data suggest that the FGF19-FGFR4 axis may be a key driver in certain forms of HCC, making the pathway an interesting, emerging molecular target for potential therapeutic intervention. A complication is that, outside of malignant disease, FGFR4 plays an important physiological role in the regulation of hepatic bile acid (BA) synthesis. FGF19 signalling via FGFR4 suppresses de novo BA production in the liver, tightly maintaining hepatic and systemic levels of these detergent-like molecules at a physiological threshold and preventing pathological complications of raised BA levels, such as cholestatic liver injury and bile acid diarrhoea. In some cases of HCC, the malignant disease causes bile duct obstruction, preventing BA secretion from the liver and resulting in cholestasis. Here, the role of FGFR4 signalling in both HCC and BA homoeostasis is discussed. The potential effects of therapeutic FGF19-FGFR4 inhibition on human hepatobiliary/gastrointestinal physiology are considered along with the potential safety implications of FGF19-FGFR4 blockade in patients with HCC.
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Macclesfield, UK.
authors.forename: Howard R
authors.initials: HR
authors.lastname: Mellor
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001647:Bile Acids and Salts / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; C117476:FGF19 protein, human; D005346:Fibroblast Growth Factors; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4
keywords: FGF19; FGFR4; bile acid; cholestasis; hepatocellular carcinoma; liver toxicity