Abstract 3894: The role of ELF3 in acquired resistance to endocrine therapy in ER-positive breast cancer

Abstract

Abstract Endocrine therapies targeting the estrogen receptor (ER) are the major treatments of ER+ breast cancer, however acquired resistance to endocrine therapy is almost unavoidable and is the main cause of death with breast cancer. The only FDA-approved selective estrogen receptor degrader (SERD) fulvestrant has been used in the second line treatment to overcome aromatase inhibitor- or tamoxifen-resistance. However, fulvestrant has poor pharmacokinetic properties, which has inspired the development of a new generation of oral SERDs including amcenestrant and giredestrant. To understand the mechanisms of acquired resistance to SERDs in ER+ breast cancer, we established ER+ breast cancer cell lines (MCF7 and T47D) resistant to fulvestrant, amcenestrant or giredestrant. We found that all of our MCF7 and T47D SERD-resistant cell lines showed cross-resistance to each of the three SERDs. We then performed multiple genome-wide profiling assays including CRISPR-KO screen, whole exome sequencing (WES), RNA-seq, ATAC-seq and H3K27ac ChIP-seq on the parental and SERD resistant cell lines. Our findings from the CRISPR-KO screens suggest that ETS transcription factor ELF3 is a potential driver of resistance to SERDs. ELF3 expression is negatively regulated by estrogen signaling. Cells that developed acquired resistance to different SERDs consistently show depletion of ER expression but also a dramatic increase of ELF3 expression, while knockdown of ELF3 in the resistant cells leads to cell growth inhibition, suggesting that ELF3 can drive cell survival in the SERD resistant cells. When comparing the open chromatin regions and active enhancer regions between SERD resistant and parental cells via ATAC-seq and H3K27ac ChIP-seq respectively, ELF3 DNA binding motif was found significantly enriched in SERD resistant cells versus parental cells further indicating that ELF3 may play an important role in the SERD resistant cells. ELF3 ChIP-seq was also performed to identify genes enriched with ELF3 binding sites in SERD resistant and parental cells. Pathway analysis of ELF3-targeted genes reveals that ELF3 may regulate cell metabolism specifically in SERD resistant cells but not in parental cells. Our study suggests that ELF3 may be a novel driver of acquired resistance to SERDs in ER+ breast cancer. Citation Format: Na Zhang, Rongbin Zheng, Myles Brown. The role of ELF3 in acquired resistance to endocrine therapy in ER-positive breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3894.