New molecular target therapeutic strategies for hepatocellular carcinoma by inhibition of FGF19/FGFR4 signaling

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17041
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Chiba University
• Principal Investigator: Hiroaki Kanzaki 千葉大学, 医学部附属病院, 医員 (10835086)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 肝細胞癌 / マルチチロシンキナーゼ阻害薬 / FGF19-FGFR4シグナル / 薬剤耐性

Outline of Final Research Achievements

Lenvatinib strongly suppressed FGF19-FGFR4 signaling in hepatoma cell lines compared to sorafenib. Patients with high serum FGF19 levels before treatment in sorafenib-treated patients had a significantly shorter prognosis than those with low serum FGF19 levels. FGF19 secretory capacity was increased and FGF19-FGFR4 signaling was also enhanced in sorafenib-resistant cell lines. Serum FGF19 levels were elevated after sorafenib treatment compared to before treatment. VEGF secretory capacity and angiogenic potential were increased in lenvatinib-resistant cell lines, but the angiogenesis suppressed by cabozantinib. Furthermore, serum VEGF levels were elevated after lenvatinib treatment compared to before treatment, and VEGF-A gene expressions were also elevated.

Free Research Field

肝細胞癌

Academic Significance and Societal Importance of the Research Achievements

FGF19-FGFR4シグナルの強力な阻害は、マルチチロシンキナーゼ阻害薬による抗腫瘍効果に重要である。また血清FGF19濃度は、ソラフェニブ投与患者における治療効果予測、生存予測のマーカーとして機能する可能性がある。ソラフェニブ耐性獲得後はFGF19-FGFR4シグナル阻害が耐性克服に重要で、レンバチニブ耐性獲得後はより強力なVEGFシグナル阻害が耐性克服に重要である可能性がある。これらにより、進行肝細胞癌患者に対するマルチチロシンキナーゼ阻害薬の使用する順番に根拠をもたらす可能性がある。