THU558 Combination Therapy Of Acetyl-CoA Synthetase Inhibitor And Fulvestrant Reverse Epigenetic Alterations Of Metastatic Breast Cancer Cells And Reduce Cancer Cell Proliferation

Abstract

Abstract Disclosure: A.N. Mogol: None. Z. Madak Erdogan: None. Endocrine therapies exploit the hormone dependencies of the cancer cells in various ways, including by targeting estrogen receptor alpha (ERα) that is expressed by approximately 70% of human breast cancers. After treatment, recurrence and metastasis are still observed in 30-40% of ER+ patients and the 5-year relative overall survival rate for these patients is just 24%. Acetyl-CoA production significantly regulates histone acetylation and gene regulation, which support tumor progression. In our previous study, we showed the synergistic effect of the ERα agonist Fulvestrant (Fulv) and Acetyl-CoA Synthase Inhibitor (ACSI) in reducing cell viability in ER+ metastatic breast cancer (MBC) cells in vitro. To study the synergistic contribution of ACSS2 to endocrine resistance, we used ChIP analysis, which showed that ACSS2 was recruited to ERα binding sites with Fulv treatment in cell line xenograft tumors and PDX samples. We used the CUT&RUN method to investigate specific protein (H3k27ac, ERα and ACSS2) and DNA interactions in ER+ MBC cells globally. Enriched chromatin samples were then used for qPCR and sequencing. Combination therapy of the ACSI and Fulv significantly altered the epigenetic landscape of the breast cancer cells in a manner to decrease cell viability. High histone acetylation at lysine 27 residue was observed in Veh treatment group and combination therapy of ACSI+Fulv further decreased the enrichment of this histone modification in classical ER binding sites. Interestingly, ACSS2 binding was increased with Fulv treatment. Targeting epigenetic alterations caused by cancer cell adaptations is a novel approach that could potentially lead to new therapies to reduce metastasis mortality. Presentation: Thursday, June 15, 2023