Abstract 4218: Discovery and in vitro characterization of FGFR/HDAC dual inhibitors for FGFR-driven cancer
Authors: Chang-Hyun Yun, Sang-Heon Kim, Seunghwan Shim, Dongkyu Shin, Seonggu Ro, Byoung-Gon Moon
Journal: Cancer Research (2025)

Abstract Gene alterations of Fibroblast growth factor receptors (FGFR) are frequently found in various solid tumors and are known as oncogenic drivers, particularly in bladder cancer and cholangiocarcinoma. Currently, pan-FGFR inhibitors are used for the treatment of FGFR2-driven intrahepatic cholangiocarcinoma and FGFR3-driven urothelial carcinoma. However, their efficacy is often limited by primary and acquired resistance mechanisms, including secondary FGFR mutation and alternative pathway activations. Secondary FGFR mutations are predominantly reported as an acquired resistance mechanism to pan-FGFR inhibitors. Additionally, substantial preclinical evidence suggests that alternative pathway activations, including EGFR, ERBB2, ERBB3, and c-MET, may significantly contribute to resistance. Interestingly, numerous preclinical studies have demonstrated that HDAC inhibitors can down-regulate their expression in certain tumor cell lines, suggesting the possibility of overcoming resistance through bypass activations. Furthermore, recent reports suggest that combining HDAC and FGFR inhibition may exhibit synergistic anti-tumor activity in both FGFR2 and FGFR3-driven tumors. Here we report the discovery and in vitro characterization of FGFR/HDAC dual inhibitors and their potential to overcome resistance via bypass activations. These compounds inhibited FGFR2 with an IC50 in the low nanomolar range in biochemical assay while sparing FGFR4. They also inhibited the proliferation of cancer cells harboring FGFR2 amplification with an IC50 in the low nanomolar range. Additionally, they inhibited HDAC1 with an IC50 in the low nanomolar range in biochemical assays and the HCT116 cell proliferation with an superior potency compared to vorinostat. To mimic drug resistance through bypass activations, SNU-16 cells were treated with EGF, HGF, or NRG1. In this model, the inhibitory efficacy of pemigatinib (an FDA approved FGFR 1-3 inhibitor) was significantly attenuated, whereas vorinostat (an FDA approved pan-HDAC inhibitor) maintained its efficacy. The greatest attenuation of efficacy was observed with EGF treatment, under which conditions some FGFR/HDAC dual inhibitors exhibited superior inhibitory efficacy compared to pemigatinib, correlating with their HDAC inhibition activity. In summary, these in vitro studies have resulted in several compounds that warrant further development for lead optimization. They also suggest that FGFR/HDAC dual inhibitors may be an option for overcoming bypass resistance in FGFR-driven tumors. Citation Format: Chang-Hyun Yun, Sang-Heon Kim, Seunghwan Shim, Dongkyu Shin, Seonggu Ro, Byoung-Gon Moon. Discovery and in vitro characterization of FGFR/HDAC dual inhibitors for FGFR-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4218.