Abstract 1414: Effect of E7090, an FGFR1-3 selective inhibitor, on resistance to a CDK4/6 inhibitor and endocrine therapy in ER(+)/HER2(-) breast cancer preclinical models

Abstract

Introduction: The fibroblast growth factor receptor (FGFR) signaling has a crucial role in proliferation, survival, migration, and drug resistance of cancer cells, as well as tumor angiogenesis. Moreover, gene alterations of FGF/FGFR were reported after treatment of a CDK4/6 inhibitor and endocrine therapy (ET) in ER(+)/HER2(-) breast cancer (BC) patients, suggesting FGF/FGFR signaling mediates resistance to these therapies. E7090, an orally available FGFR1-3 selective inhibitor, is currently under evaluation in a Phase 2 study in patients with unresectable advanced or metastatic cholangiocarcinoma with FGFR2 gene fusion (NCT04238715), and a Phase 1 study as a monotherapy or in combination with fulvestrant (FUL) or exemestane for ER(+)/HER2(-) BC patients (NCT04572295). In this study, we present the roles of FGF/FGFR signaling in resistance to a CDK4/6 inhibitor and/or ET, and activities of E7090 on drug resistance in preclinical ER(+)/HER2(-) BC cell lines and PDx models. Results: Antitumor activities of E7090 (25 or 50mg/kg, Q1Dx14 or x21, p.o.) were evaluated using five ER(+)/HER2(-) BC PDx models, OD-BRE-0438, -0450, -0188, -0704, and IM-BRE-556 with or without prior treatment of FUL (5 mg/mouse, Q7Dx2, s.c.)+palbociclib (PAL, 100mg/kg, Q1Dx14, p.o.). Among them, OD-BRE-0438 and -0704 showed higher sensitivities to E7090 with prior FUL+PAL than without it, and E7090 showed tumor regression in the OD-BRE-0438 model only with prior FUL+PAL. In these two models, FUL+PAL treatment upregulated expressions of several FGF ligands mRNA (qPCR) and FGFRs protein (IHC) in tumors. To evaluate the activities of FGF/FGFR signaling on sensitivities to FUL or FUL+PAL, in vitro cell proliferation assay using ER(+)/HER2(-) BC cell lines, MCF-7, ZR-75-1, and HCC1428 were performed in the presence of FGF2 and FGF10, and decreased sensitivities to FUL or FUL+PAL were observed. Furthermore, co-treatment with E7090 restored the sensitivity to those drugs in cultured cell lines. In consistent with in vitro results, FUL in combination with E7090 showed a combination antitumor activity in the OD-BRE-0438 model, in which expressions of several FGF ligands mRNA and FGFR2 protein in tumors showed a tendency of upregulation by FUL. Conclusion: In ER(+)/HER2(-) BC PDx models, FGFs/FGFRs expression in tumors were induced by treatment of FUL and/or PAL, and antitumor activity of E7090 was enhanced with prior FUL+PAL. In vitro study using cultured ER(+)/HER2(-) BC cell lines indicated that sensitivity against FUL or FUL+PAL was decreased by FGFR activation. Furthermore, a combination antitumor activity of E7090 and FUL was observed in the OD-BRE-0438 model. These data suggest that activation of FGF/FGFR signaling confer the resistance to a CDK4/6 inhibitor and/or ET, and E7090 shows antitumor activity against ER(+)/HER2(-) BC with prior a CDK4/6 inhibitor and/or ET. Citation Format: Satoshi Kawano, Sayo Fukushima, Kyoko Nishibata, Ryu Gejima, Yuki Niwa, Yasuhiro Funahashi, Saori Watanabe Miyano. Effect of E7090, an FGFR1-3 selective inhibitor, on resistance to a CDK4/6 inhibitor and endocrine therapy in ER(+)/HER2(-) breast cancer preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1414.

CDK4/6 inhibitor resistance: A bibliometric analysis

“…Secondly, due to the overexpression of CDK2 after drug resistance, co-inhibition of CDK2 has also become a director of research (47)(48)(49)(50). The rest of the mentioned therapies include MEK inhibition, FGFR inhibition, MDM2 inhibition, CDK7 inhibition, immunotherapy, etc (41,(51)(52)(53)(54)(55)(56). CDK4/6 inhibitor resistance involves multiple pathways and multiple aspects.…”