Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Hepatocellular carcinoma (HCC) is a major global cancer mortality cause.
• The role of Fibroblast Growth Factor 19 (FGF19) receptor FGFR4 in hepatocarcinogenesis is suggested but not clinically confirmed.
• Targeted therapies for HCC lack a clinically validated oncogenic driver.

Purpose of the Study:

• To investigate the clinical dependence of human HCC on FGFR4.
• To identify mechanisms of acquired resistance to FGFR4 inhibition.
• To validate FGFR4 as a therapeutic target in HCC.

Main Methods:

• Treatment of HCC patients with fisogatinib, a potent and selective FGFR4 inhibitor.
• Genomic analysis of tumors from patients experiencing disease progression.
• In vitro and in vivo validation of identified resistance mutations.
• Testing of a gatekeeper-agnostic pan-FGFR inhibitor in HCC xenografts.

Main Results:

• Fisogatinib demonstrated clinical benefit and tumor regression in HCC patients with aberrant FGF19 expression.
• On-target mutations in FGFR4 gatekeeper and hinge-1 residues mediated acquired resistance to fisogatinib.
• These mutations conferred resistance both in vitro and in vivo.
• A pan-FGFR inhibitor showed efficacy against HCC xenografts harboring these resistance mutations, indicating continued pathway dependence.

Conclusions:

• This study is the first to demonstrate on-target FGFR4 kinase domain mutations causing acquired resistance to targeted therapy.
• FGF19-FGFR4 pathway activation is validated as an oncogenic driver in HCC.
• Further investigation of fisogatinib and development of next-generation FGFR4 inhibitors are warranted for HCC treatment.