Targeted inhibition of the FGF19-FGFR4 pathway in hepatocellular carcinoma; translational safety considerations
1Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Macclesfield, UK.
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.
Insights
Targeting the FGF19-FGFR4 pathway may treat hepatocellular carcinoma (HCC). However, inhibiting this axis could disrupt bile acid (BA) homeostasis, impacting liver function and causing gastrointestinal issues.
Area of Science:
- Hepatology
- Oncology
- Gastroenterology
Background:
- Hepatocellular carcinoma (HCC) is a major cause of cancer mortality, necessitating novel therapeutic strategies.
- The FGF19-FGFR4 signaling pathway is implicated as a driver in specific HCC subtypes, presenting a potential therapeutic target.
- FGFR4 also plays a crucial physiological role in regulating hepatic bile acid (BA) synthesis, maintaining homeostasis outside of malignancy.
Purpose of the Study:
- To discuss the dual role of FGFR4 signaling in both HCC pathogenesis and bile acid homeostasis.
- To explore the potential physiological and safety implications of inhibiting the FGF19-FGFR4 pathway in patients with HCC.
Main Methods:
- Literature review and discussion of existing data on the FGF19-FGFR4 axis in HCC and normal physiology.
- Analysis of the interplay between FGFR4 signaling, bile acid metabolism, and liver function.
- Consideration of potential therapeutic interventions targeting FGF19-FGFR4.
Main Results:
- FGF19-FGFR4 signaling is a potential therapeutic target in certain HCCs.
- Inhibition of FGF19-FGFR4 may disrupt normal bile acid synthesis and homeostasis.
- Therapeutic blockade could lead to adverse effects on hepatobiliary and gastrointestinal physiology.
Conclusions:
- The FGF19-FGFR4 axis represents a promising target for HCC therapy but requires careful consideration of its physiological roles.
- Understanding the impact of therapeutic inhibition on bile acid metabolism is critical for patient safety.
- Further research is needed to balance the anti-cancer benefits with potential side effects in HCC patients.
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