Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is an aggressive cancer with poor prognosis and the third most common cause of cancerrelated deaths worldwide [1]
Upon ligand binding to FGFR, the receptor is dimerized for the autophosphorylation and recruitment of adaptor proteins such as FGFR substrate 2 (FRS2), which activates several intracellular signaling pathways involved in cell growth, differentiation, and
Kinase selectivity was investigated against a panel of 128 human kinases, and the kinases that showed more than 50% inhibition by ASP5878 (200 nmol/L) were FGFRs, VEGFR2, and FMS (Table 1)
Summary
Hepatocellular carcinoma (HCC) is an aggressive cancer with poor prognosis and the third most common cause of cancerrelated deaths worldwide [1]. Surgical resection is the most successful treatment for early-stage HCC; 70% of patients have recurrence after 5 years [2, 3]. A broadspectrum kinase inhibitor, has been approved as a moleculartargeted drug for surgically unresectable HCC and has been shown to improve the duration of survival to 10.7 months in comparison with 7.9 months in patients receiving placebo in a phase 3 trial [4]. The signaling pathway activated by FGFRs and their cognate ligands, i.e., fibroblast growth factors (FGF), plays an important role in the course of development from early embryogenesis to the formation of various organs. Upon ligand binding to FGFR, the receptor is dimerized for the autophosphorylation and recruitment of adaptor proteins such as FGFR substrate 2 (FRS2), which activates several intracellular signaling pathways involved in cell growth, differentiation, and
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