Abstract 661: Synergistic antitumor activity of futibatinib, an FGFR1-4 inhibitor, and TAS-117, a selective AKT inhibitor, in <i>FGFR</i>-deregulated cancer models
Authors: Junya Iwasaki, Takuya Kuramoto, Toshiharu Komori, Hitoshi Saito, Hiroshi Hirai
Journal: Cancer Research (2020)

Abstract Background: TAS-117 is a potent oral allosteric non-ATP inhibitor selective for AKT. A phase 1 study with TAS-117 is ongoing in patients with endometrial cancer and ovarian clear cell carcinoma. Futibatinib (TAS-120) is a selective, irreversible small-molecule fibroblast growth factor receptor (FGFR) 1-4 inhibitor, with potent antiproliferative activity in preclinical models with FGFR aberrations. Phase 2 studies are ongoing in patients with various FGFR-deregulated cancers. We evaluated the antitumor activity of futibatinib plus TAS-117 in FGFR-aberrant cancer models. Methods: Effects of futibatinib plus TAS-117 were investigated in human endometrial FGFR2-N549K-mutated AN3CA cancer cells and small-cell lung cancer FGFR1-amplified DMS114 cells. Activation of RAS and PI3K pathways was assessed by detecting phosphorylation of ERK1/2, AKT, and S6. Antitumor combination indices (CI) for cell viability over time were determined with the Chou-Talalay median-effect method and CalcuSyn software; a CI&amp;lt;0.9 indicates synergy. Antitumor effects of futibatinib (15 mg/kg/d) plus TAS-117 (4 or 8 mg/kg/d) or monotherapy were also evaluated in a mouse AN3CA xenograft model. FGFR signaling, apoptosis (via caspase activity and PARP cleavage), and relative tumor volume (RTV; compared with Day 0) were assessed. Results: Futibatinib and TAS-117 synergistically increased cell death and decreased cell growth in AN3CA (CI&amp;lt;0.40) and DMS114 (CI&amp;lt;0.40) cells, respectively. Apoptosis induction was readily detected with futibatinib plus TAS-117 in AN3CA cells, but low activity was observed with monotherapy. In both AN3CA and DMS114 cells, futibatinib suppressed ERK1/2, but not AKT phosphorylation; the futibatinib plus TAS-117 combination suppressed phosphorylation of both ERK1/2 and AKT. In AN3CA xenografts, combination therapy inhibited the FGFR, PI3K, and MEK pathways. Futibatinib plus TAS-117 increased PARP cleavage more than monotherapy. Compared with Day 0, RTV on Day 15 was 60.71 in the control, 13.40 with futibatinib monotherapy, and 33.63 with TAS-117 (8 mg/kg/d) monotherapy. Treatment with 3 different futibatinib plus TAS-117 combination dosing regimens resulted in marked reductions in RTVs on Day 15 (2.16, 0.53, and 0.22). Conclusions: Our findings suggest that futibatinib plus TAS-117 has synergistic antitumor effects in FGFR-aberrant tumors. A phase 1/2 study of this combination in advanced solid tumors (JapicCTI-194864) is ongoing. Citation Format: Junya Iwasaki, Takuya Kuramoto, Toshiharu Komori, Hitoshi Saito, Hiroshi Hirai. Synergistic antitumor activity of futibatinib, an FGFR1-4 inhibitor, and TAS-117, a selective AKT inhibitor, in FGFR-deregulated cancer models [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 661.