Genetic abnormalities (gene fusion, mutation and amplification) of fibroblast growth factor receptor (FGFR) family members are known to cause constitutive activation of their signaling pathways, which play an important role in proliferation, survival and migration of cancer cells, as well as tumor angiogenesis. Several recent studies have identified that FGFR2 gene fusions were found in about 10% of intrahepatic cholangiocarcinoma and acted as oncogenes. E7090, an orally available FGFR1, 2 and 3 inhibitor, whose chemical-structure and basic kinase inhibitory profile have been disclosed at AACR2015, is currently under a first-in-human study (NCT02275910). The antitumor activity of E7090 against NIH3T3 and human cholangiocarcinoma cells harboring FGFR2-fusion genes was investigated. NIH3T3 cells stably infected of five FGFR2-fusion genes (FGFR2-AHCYL1, FGFR2-BICC1 type1, FGFR2-BICC1 type2, FGFR2-TXLNA, or FGFR2-KCTD1), all of which were discovered in human intrahepatic cholangiocarcinoma patients, were successfully established and exhibited anchorage-independent cell growth in soft agar assay. E7090 revealed an inhibitory activity on soft agar colony formation of these cells with IC50 values of 0.9 to 17.3 nmol/L in a dose dependent manner. E7090 also reduced activation of downstream pathways of FGFR signaling (MAPK and STAT3) in these cells. Subcutaneous transplantation of FGFR2-BICC1 type2, FGFR2-TXLNA, or FGFR2-KCTD1 expressing cells into immune-deficient mice produced tumor growth, and then oral administration of E7090 at 12.5, 25 and 50 mg/kg showed significant tumor growth inhibition. Finally, antitumor activity of E7090 was examined in a patient derived xenograft (PDX) model of human cholangiocarcinoma harboring FGFR2-BICC1 fusion gene. E7090 also showed dose-dependent antitumor activity and more than 50% of tumor regression was achieved at a dose of 50 mg/kg. In conclusion, E7090 showed potent antitumor activity against FGFR2-fusion genes found in intrahepatic cholangiocarcinoma both in vitro and in vivo models, suggesting that E7090 may provide therapeutic opportunities for cholangiocarcinoma harboring FGFR2-fusion genes.

Citation Format: Saori W. Miyano, Yasuhito Arai, Junji Matsui, Tatsuhiro Shibata. E7090, a novel and selective FGFR inhibitor, for the treatment of cholangiocarcinoma cells harboring FGFR2-fusion genes [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 2095. doi:10.1158/1538-7445.AM2017-2095