Abstract 3308: A selective FGFR1/2 degrader overcomes endocrine resistance in ER+/FGFR1-amplified andFGFR1/2-mutant breast cancer

Abstract FGFR1 amplification and FGFR1/2 activating mutations are associated with resistance to antiestrogens in the estrogen receptor-positive (ER+) breast cancer. In this study, we investigated selective degradation of FGFR1/2 using the proteolysis-targeted chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy to overcome resistance to antiestrogens in ER+ breast cancers harboring FGFR1-amplification or FGFR1/2 activating mutations. Treatment of ER+/FGFR1-amplified CAMA1 and MDA-MB-134 breast cancer cells with DGY-09-192 degraded FGFR1 and suppressed phosphorylation of FGFR1 and its downstream targets FRS2, AKT, and ERK1/2. DGY-09-192-mediated FGFR1 degradation were rescued by a proteasome inhibitor, MG132, suggesting that the antitumor activity of DGY-09-192 depends on proteasome-mediated degradation. Growth of CAMA1 and MDA-MB-134 cells were modestly inhibited by single-agent DGY-09-192 or the ER degrader fulvestrant, but the combination completely arrested cell proliferation. Treatment of female NSG mice bearing established ER+/FGFR1-amplified patient-derived xenografts (PDXs) with single-agent DGY-09-192 (40 mg/kg/day, i.p.) or fulvestrant (5 mg/week, s.c.) delayed tumor growth, respectively. However, treatment with DGY-09-192 + fulvestrant induced tumor regression in all mice (n=7), suggesting that a FGFR1 degrader plus an antiestrogen can serve as an effective therapeutic combination for ER+/FGFR1-amplified breast cancer. Next, we examined whether ER+ breast cancer cells harboring FGFR1/2 hotspot mutations are sensitive to DGY-09-192. Ectopic expression of FGFR1N546K, the most common FGFR1 mutation in breast cancer, activated FGFR1 signaling and induced resistance to fulvestrant compared to MCF7 cells transduced with wild-type FGFR1. EFM-19 cells harboring FGFR2K659E exhibited resistance to fulvestrant in vitro. Treatment of both cell lines with DGY-09-192 degraded the mutant FGFR1N546K and FGFR2K659E, respectively, blocked phosphorylation of the FGFR downstream targets, and markedly inhibited cell proliferation. These results suggest that PROTAC-mediated degradation of FGFR1/2 effectively blocks the growth of ER+, FGFR1/2-mutant breast cancers resistant to antiestrogens. Conclusions: DGY-09-192 induced FGFR1/2 degradation and blocks FGFR downstream signaling in ER+/FGFR1-amplified and FGFR1/2-mutant breast cancer cells. The combination of DGY-09-192 and fulvestrant exhibited superior antitumor effects relative to each monotherapy alone in vitro and/or in vivo. Therefore, PROTAC-mediated FGFR1/2 degradation represents a promising therapeutic strategy for ER+ breast cancers harboring FGFR1-amplification or FGFR1/2 activating mutations. Citation Format: Yasuaki Uemoto, Chang-Ching Lin, Bingnan Wang, Dan Ye, Emmanuel Bikorimana, Alberto Servetto, Luigi Formisano, Fabiana Napolitano, Rosario Chica Parrado, Saurabh Mendiratta, Chuo Chen, Ariella B. Hanker, Carlos L. Arteaga. A selective FGFR1/2 degrader overcomes endocrine resistance in ER+/FGFR1-amplified andFGFR1/2-mutant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3308.