Abstract P3-03-08: A large-scale functional screen to identify resistance mechanisms to selective estrogen receptor degraders fulvestrant and GDC-810 in ER+ breast cancer

Abstract

Abstract Therapies that target the estrogen receptor provide clinical benefit and improved survival for patients with estrogen receptor-positive (ER+) breast cancer, yet drug resistance remains a challenging problem, leading to disease relapse and mortality. In recent years, the selective estrogen receptor degrader (SERD) fulvestrant has become an important therapeutic option for patients with resistant ER+ metastatic breast cancer, and newer oral SERDs such as GDC-810 are currently being tested in clinical trials. The mechanisms of intrinsic and acquired resistance to SERDs remain to be fully elucidated. We conducted a large-scale lentiviral open reading frame (ORF) screen to identify genes whose overexpression confers drug resistance to either fulvestrant or GDC-810 in the ER+ breast cancer cell line T47D. The lentivral ORF expression library used in this study consists of 16,544 barcoded ORFs, including 2,767 ORFs with mutations. The initial screen yielded 72 genes resulting in resistance to fulvestrant and 85 genes resulting in resistance to GDC-0810, with 44 genes overlapping. The top ranked-genes included multiple genes belonging to the PI3K/Akt, ERbB/HER, and FGF/FGFR pathways as well as genes involved in cell cycle progression. Fibroblast growth factor receptor 1 (FGFR1) amplifications are frequently observed in patients with ER+ breast cancer, and have previously been implicated in resistance to endocrine therapies. Several FGFs (FGF3, FGF6, FGF10, and FGF22) were among the top-ranked resistance genes for both fulvestrant and GDC-0810, suggesting that activation of the FGFR signaling pathway may render cells resistant to fulvestrant and GDC-810. In the presence of FGF2, overexpression of FGFR1 in ER+ breast cancer cells resulted in resistance to both fulvestrant and GDC-0810. The ability of an FGFR inhibitor to overcome FGFR-mediated resistance to SERDs is being tested. Additional potential resistance genes identified in the ORF screen are also being validated. In summary, a whole-genome functional resistance screen has identified several candidate genes and pathways that may cause resistance to fulvestrant and GDC-810. Several of these candidates, such as FGFR1, are also found in patients who develop resistance to SERDs, suggesting rational combination therapies to overcome or preempt SERD resistance. Citation Format: Mao P, Quartey Q, Cohen O, Piccioni F, Wagle N. A large-scale functional screen to identify resistance mechanisms to selective estrogen receptor degraders fulvestrant and GDC-810 in ER+ breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-08.