Abstract 1805: Antitumor activity of lenvatinib mesilate in human hepatocellular carcinoma preclinical models
Authors: Matsuki Masahiro , Yamamoto Yuji , Hoshi Taisuke , Kimura Takayuki , Funahashi Yasuhiro , Matsui Junji 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) is a one of the leading causes of cancer death worldwide; however systemic therapeutic option for unresectable HCC is limited. Liver carcinogenesis is a complex process and various pathways have been found to be deregulated. Of those pathways, aberrant activation of fibroblast growth factor 19 (FGF19)/FGF receptor 4 (FGFR4) axis has been hypothesized to participate in the development of HCC with poor prognosis. Lenvatinib mesilate (lenvatinib) is an orally administered multi-targeted tyrosine kinase inhibitor (TKI) that selectively inhibits vascular endothelial growth factor receptors (VEGFR)1-3, FGFR1-4, platelet-derived growth factor receptor (PDGFR)α, RET, and KIT. In this study, we investigated the activities of lenvatinib against human HCC cells with or without amplification/overexpression of FGF19 gene in vitro and in vivo. Lenvatinib inhibited in vitro proliferation of human HCC cell lines Hep 3B2.1-7 and HuH-7 with IC50 values of 0.23 and 0.42 μmol/L (0.086 and 0.16 μmol/L as unbound IC50), respectively, whereas it did not show potent antiproliferative activity against PLC/PRF/5 (IC50 &gt;10 μmol/L). Both Hep 3B2.1-7 and HuH-7 were reported to have an amplification of FGF19 gene and their cell growth was dependent on FGF19/FGFR4 axis. Sorafenib inhibited in vitro proliferation of the 3 HCC cell lines with IC50 values of 2.2 - 5.3 μmol/L (0.59 - 1.4 μmol/L as estimated unbound IC50 based on previously reported protein binding). Next, antitumor activity was evaluated in 2 human HCC cell line (PLC/PRF/5 and Hep 3B2.1-7) xenograft models. Lenvatinib treatments at 1 - 100 mg/kg resulted in tumor growth inhibition with a maximal antitumor effect giving a minimum T/C value (minT/C) of 14% via its antiangiogenic activity in the PLC/PRF/5 model, and at 3 - 30 mg/kg with minT/C of 31% in the Hep 3B2.1-7 model. Sorafenib showed significant antitumor effect at doses ≥30 mg/kg with minT/C of 30% in the PLC/PRF/5 model, and at 10 and 30 mg/kg with minT/C of 47% in the Hep 3B2.1-7 model. Finally, we tested antitumor activity in HCC patient-derived xenograft (PDX) model (LI0050), and PDX-derived cell line (LIXC-012) xenograft model with FGF19 overexpression in mice. Lenvatinib significantly inhibited the tumor growth of LI0050 at 10 and 30 mg/kg with minT/C of 33%, and that of LIXC-012 at 3 - 30 mg/kg with minT/C of 25%. Treatment with sorafenib at 30 mg/kg was intolerable in LI0050 model, and sorafenib showed significant antitumor activity at 30 mg/kg with T/C of 55%, but not 10 mg/kg in the LIXC-012 model. In conclusion, these results indicate that lenvatinib has potent preclinical antitumor activity in human HCC xenograft models with or without amplification/overexpression of FGF19. Furthermore, the maximum antitumor effect of lenvatinib was greater than that of sorafenib in this study. Direct effect of lenvatinib on proliferation of HCC cells with an aberrant FGF signaling pathway in tumor warrants further investigation.
Citation Format: Masahiro Matsuki, Yuji Yamamoto, Taisuke Hoshi, Takayuki Kimura, Yasuhiro Funahashi, Junji Matsui. Antitumor activity of lenvatinib mesilate in human hepatocellular carcinoma preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1805. doi:10.1158/1538-7445.AM2017-1805