Abstract A172: Preclinical antitumor activity of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, in FGF19-expressing hepatocellular carcinoma

Background: Fibroblast growth factor (FGF) / FGF receptor (FGFR) gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers. Recently, FGF19 overexpression was observed in approximately 50% of hepatocellular carcinoma (HCC) patients. The FGF19-FGFR4 signaling has been implicated in the development of HCCs in mice. FGFR4 kinase inhibitors are expected to be a targeted therapy for FGF19-expressing HCC. A phase I clinical trial of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, is ongoing (NCT02038673). Method: We tested selectivity of ASP5878 among 128 kinases and sensitivity of ASP5878 on cell proliferation of HCC cell lines. Activation of FRS2 and ERK, downstream molecules of FGFR signaling, and PARP cleavage in FGF19 expressing HCC cell lines were evaluated with Western blotting. In vivo antitumor effects of ASP5878 were examined in HCC subcutaneous xenograft and orthotopic inoculation mouse models. Finally, plasma levels of FGF19 were measured after dosing ASP5878. Results: Among 128 kinases, only 9 kinases including FGFR1-4 and FGFR3/4 mutations were inhibited more than 50% by ASP5878 (200 nmol/L). The IC 50 values of ASP5878 against FGFR1, 2, 3 and 4 kinases were 0.47, 0.60, 0.74 and 3.5 nmol/L, respectively. ASP5878 inhibited cell proliferation of HCC cell lines with FGF19 overexpression. IC 50 values were 8.5, 27, and 21 nmol/L in Hep3B2.1-7, HuH-7 and JHH-7, respectively. ASP5878 inhibited activation of downstream signaling molecules, FRS2 and ERK, and induced apoptosis in Hep3B2.1-7 cells. Oral dosing of ASP5878 at 3 mg/kg induced sustained tumor regression in the Hep3B2.1-7 subcutaneous xenograft model, which was poorly responsive to sorafenib. In an HuH-7 orthotopic inoculation mouse model, ASP5878 induced complete tumor regression and dramatically extended the survival. In addition, oral dosing of ASP5878 reduced plasma levels of FGF19 in the HuH-7 subcutaneous xenograft model. Conclusion: These results suggest that ASP5878 is a potentially effective therapeutic agent for FGF19-expressing HCC. Citation Format: Takashi Futami, Hidetsugu Okada, Rumi Kihara, Tatsuya Kawase, Ayako Nakayama, Tomoyuki Suzuki, Minoru Kameda, Nobuaki Shindoh, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu. Preclinical antitumor activity of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, in FGF19-expressing hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A172.