Combination synergy of FGFR inhibitors with other therapeutic agents in FGFR-deregulated cancer models

Background: Benefitting from the emerging role of comprehensive genomic profiling in the era of precision medicine, genomic aberrations (amplification, mutation and fusion) of fibroblast growth factor (FGF) receptor (FGFR) are frequently found in multiple solid tumors. FGFR selective inhibitors targeting these alterations showed inspiring clinical benefits. Currently three FGFR inhibitors have been approved as monotherapy to treat locally advanced or metastatic urothelial carcinoma with FGFR2/3 alterations (erdafitinib) and unresectable cholangiocarcinoma with FGFR2 fusions (pemigatinib and infigratinib) through accelerated approval process. Despite the beneficial effects of FGFR inhibitors in clinic, the limited antitumor spectrum and the potential drug resistance are major concerns. Hence, combination with other therapeutic agents to overcome these limitations are needed. Here we describe a cellular-based study to identify the potential combination partners for both pan-FGFR and FGFR4 selective inhibitors. Materials and methods: We tested a set of small molecule inhibitors that targeting the components related to FGFR pathway, including but not limited to PI3Ki, AKTi, mTORi, SHP2i, SOS1i, MEKi, CDK4/6i and METi, in cellular combination experiments with a pan-FGFR inhibitor ABSK091 (formerly AZD4547) or a FGFR4 selective inhibitor ABSK011 for various FGFR-deregulated models, including endometrial cancer cells harboring FGFR2 mutations, gastric cancer cells with FGFR2 amplification and overexpression, bladder cancer cells bearing FGFR3 fusion and hepatocellular carcinoma (HCC) cells with FGF19 amplification and overexpression. Cell growth inhibition was measured and synergistic effect was analyzed. Results: Synergistic effects on cell growth inhibition were observed in ABSK091 in combination with several agents including copanlisib, MK2206, onatasertib, SHP099, TNO155, BI3406. When evaluating agents in combination with ABSK011 in HCC models, we found that several MAPK pathway inhibitors showed synergy while inhibitors targeting PI3K-AKT pathway did not show such effect. Enhanced downstream signaling inhibition were confirmed in these synergistic combinations, which were consistent with cell growth inhibition results. Conclusions: Our findings suggest that FGFR selective inhibitors in combination with broad target therapeutic agents may offer additional therapeutic benefits in various FGFR-deregulated cancers. No conflict of interest.