Abstract 2003: Chromatin based targeting of a master regulatory complex in estrogen receptor epithelial ovarian cancer

Abstract

Abstract Ovarian cancer remains a significant contributor to cancer-related mortality in the United States, with low survival rates over the past decades. Hormonal therapies targeting estrogen receptors have shown limited efficacy. To explore mechanism of the inefficacy, our approach involved investigating ESR1 degradation within the higher order chromatin structure formed by Megacomplex. We identified a 1.3MDa Megacomplex containing ESR1, FOXA1 and PITX1, with colocalization at 2,440 genomic positions within the PEO4 cell line. Unlike cytoplasmic ESR1, the nuclear form was degraded minimally by ICI182780 (ICI), moreover, ESR1 incorporated into the Megacomplex macromolecule was least degraded. We hypothesized that this resistance might be due to sequestration within the Megacomplex, thereby preventing ICI from effectively targeting ESR1. Addition of a small molecule inhibitor of active chromatin, JQ1, in combination with ICI effectively enhanced the degradation of ESR1 within Megacomplex. The combination stopped nuclear occupancy of ESR1 and also degraded the cytoplasmic protein, thus breaking the ESR1 signaling circuit responsible for tumor cell proliferation. Pathway enrichment results consistently identified similar gene sets obtained independently for RNA-seq analysis after ESR1 modulation, and ChIP-seq analysis of Megacomplex bound genes. Likewise, proteins enriched within the Megacomplex macromolecule, as revealed from mass-spec analysis, returned similar pathway enrichments, directly implicating Megacomplex in ESR1 ovarian cancer gene regulation. We conclude, ESR1 in Megacomplex is resistant to ICI and sensitized by combining ICI with JQ1. This combined treatment strategy showed inhibition of cell proliferation and viability by uncovering ESR1 within the Megacomplex, thus elucidating a novel drug resistance mechanism. Citation Format: Sushil K. Jaiswal, Kevin Fedkenheuer, Ronak Khamar, Hua Tan, Valer Gotea, Abdel Elkahloun, Christina Annunziata, Laura Elnitski. Chromatin based targeting of a master regulatory complex in estrogen receptor epithelial ovarian 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 2003.