Abstract 5375: Precision run-on sequencing (PRO-seq) analysis of a treatment time course in ER+ breast cancer cell lines reveals the transcriptional changes underlying response to complete estrogen receptor antagonist (CERAN) OP-1250

Abstract OP-1250 is an orally-bioavailable complete estrogen receptor antagonist (CERAN) previously shown to shrink wild-type and Y537S mutant estrogen receptor-positive (ER+) tumors in multiple preclinical xenograft models. To better understand the effects of OP-1250 treatment on ER+ breast cancer cells, we used precision run-on sequencing (PRO-seq) to profile the direct transcriptional effects of OP-1250 in two commonly used breast cancer cell lines, MCF7 and CAMA-1. PRO-seq detects nascent RNA, and thus can detect changes at shorter timescales than traditional RNA-seq methods. We conducted PRO-seq 15 minutes, 1 hour, 6 hours and 24 hours after administration of OP-1250, estradiol, fulvestrant and tamoxifen to compare the effects of these compounds across the two cell lines. OP-1250 was administered in the absence of estradiol and after estradiol pretreatment to generate a detailed profile of the time course of its activity. We identified genes that display early transcriptional changes in response to the compounds tested, many of which have been previously identified as estrogen response genes. At later time points we observed transcriptional changes consistent with modulation of pathways involved in cell cycle progression. We show that OP-1250 treatment reverses the estradiol-induced transcriptional changes associated with estrogen receptor activation and chronicle the time course of these changes. Finally, we show greater similarity in the transcriptional changes induced by CERANs OP-1250 and fulvestrant compared to tamoxifen, as well as cell line-specific differences in estrogen response and response to anti-estrogen treatment. These data provide additional insights into the mechanisms of OP-1250 action on ER+ cell lines and patient tumors. OP-1250 is currently in a Phase I/II clinical trial for the treatment of ER+ breast cancer. Citation Format: Alison D. Parisian, Caitlin Miller, Fabian Ortega, Leslie Hodges-Gallagher, Susanna Barratt, Joey Azofeifa, Peter J. Kushner, David Kulp, Cyrus L. Harmon. Precision run-on sequencing (PRO-seq) analysis of a treatment time course in ER+ breast cancer cell lines reveals the transcriptional changes underlying response to complete estrogen receptor antagonist (CERAN) OP-1250 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5375.