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