ASP5878, a Novel Inhibitor of FGFR1, 2, 3, and 4, Inhibits the Growth of FGF19-Expressing Hepatocellular Carcinoma

Hepatocellular carcinoma is an aggressive Cancer with poor prognosis. Fibroblast Growth Factor 19, a member of the Fibroblast Growth Factor family, is a ligand for Fibroblast Growth Factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of Fibroblast Growth Factor receptors 1, 2, 3, and 4 that is under development. It inhibits Fibroblast Growth Factor receptor 4 kinase activity with an IC₅₀ of 3.5 nmol/L. ASP5878 potently suppressed the growth of the Fibroblast Growth Factor 19-expressing hepatocellular carcinoma cell lines Hep3B2.1-7, HuH-7, and JHH-7. In the Hep3B2.1-7 cell line, ASP5878 inhibited the phosphorylation of Fibroblast Growth Factor receptor 4 and its downstream signaling molecules as well as induced Apoptosis. Oral administration of ASP5878 at 3 mg/kg induced sustained tumor regression in a subcutaneous xenograft mouse model using Hep3B2.1-7. In HuH-7, an orthotopic xenograft mouse model, ASP5878 induced complete tumor regression and dramatically extended the survival of the mice. These results suggest that ASP5878 is a potentially effective therapeutic agent for hepatocellular carcinoma patients with tumors expressing Fibroblast Growth Factor 19. Mol Cancer Ther; 16(1); 68-75. ©2016 AACR.