Abstract 659: Synergistic antitumor activity of futibatinib (TAS-120), a FGFR1-4 inhibitor, and PI3K pathway inhibitors

Abstract

Abstract Background: Futibatinib, a selective irreversible small-molecule fibroblast growth factor receptor (FGFR) 1–4 inhibitor is currently being investigated in phase 2 studies in patients with various FGFR-deregulated cancers. FGFRs use the PI3K pathway to promote cell growth and survival, suggesting that a combination of futibatinib with PI3K pathway inhibitors may result in synergistic activity. Therefore, we investigated the antitumor effects of futibatinib plus PI3K pathway inhibitors, everolimus (mTOR inhibitor) or MK2206 (AKT inhibitor). Methods: Human endometrial FGFR2-N549K-mutated AN3CA cancer cells were treated with futibatinib plus either everolimus or MK2206 or with each agent alone. AKT, ERK, mTOR, and S6 phosphorylation, cell viability, and apoptosis (via caspase-3/7 activity) were assessed. Cell growth inhibition was measured and combination indices (CIs) determined using CalcuSyn software; a CI<0.9 indicates synergy. Antitumor activity of futibatinib plus everolimus in ANC3A xenografts was evaluated by assessing relative tumor volume (RTV). Results: In ANC3A cells, the combination of futibatinib with MK2206 inhibited AKT phosphorylation; futibatinib plus either MK2206 or everolimus inhibited mTOR phosphorylation to a greater degree than monotherapy. Apoptosis induction by caspase-3/7 was readily detected with futibatinib plus MK2206, but low to no activity was observed with either agent alone. A synergistic effect on cell growth inhibition was observed for futibatinib plus everolimus (CI=0.26) or MK2206 (CI=0.14). In AN3CA xenografts, there was a significant (P<0.05) decrease in RTV with futibatinib plus everolimus vs monotherapy (Table). Table.Relative tumor volume in AN3CA mouse xenografts treated with futibatinib or everolimus or combination therapyTreatment (mg/kg/d)Relative tumor volumeDay 0Day 3Day 6Day 10Day 15Control14.657.8116.4937.77Futibatinib (15)a13.084.516.8412.59Futibatinib (50)a12.292.703.154.76Everolimus (2)a12.664.046.3410.24Futibatinib + Everolimus (15 + 2)b11.841.921.681.91Futibatinib + Everolimus (50 + 2)b11.501.310.840.72aDays 1–14 (oral);bDays 1–14 + Days 1–14 (both oral). Conclusions: The combination of futibatinib plus a PI3K pathway inhibitor resulted in synergistic antitumor effects. These data are encouraging and can serve as a basis for investigating the combination of PI3K pathway inhibitors with futibatinib. Citation Format: Akihiro Miura, Hiroshi Sootome, Toshiharu Komori, Hiroaki Ochiiwa, Hiroshi Hirai. Synergistic antitumor activity of futibatinib (TAS-120), a FGFR1-4 inhibitor, and PI3K pathway inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 659.