Abstract 375: BRD8 chromatin regulator mediates anti-HER2 response in HR+/HER2+ breast cancer.

Abstract Chromatin remodeling complexes are critical regulators of transcription and therapeutic resistance in cancer, yet the mechanisms governing their recruitment and activity remain poorly understood. Here, we identify BRD8, a largely uncharacterized bromodomain protein within the EP400 chromatin remodeling complex, as a master regulator of treatment-induced transcriptional reprogramming in hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer. Using integrative multi-omics approaches—including paired single-cell RNA-seq and ATAC-seq, comprehensive ChIP-seq profiling, and functional genomics—we uncover a novel epigenetic mechanism whereby BRD8 orchestrates chromatin accessibility and transcription factor cooperation to drive therapeutic resistance. BRD8 depletion reduces H2A.Z acetylation and disrupts interactions between the EP400 complex and key transcription factors. Through both ER-dependent and ER-independent pathways, BRD8 cooperates with H2A.Z and acetylated H2A.Z (H2A.Zac) to facilitate recruitment of the EP400 complex to transcription factors including ER, FOXA1, and ETS family members, thereby promoting H2A.Z acetylation, chromatin accessibility, and expression of growth-promoting genes. BRD8 expression is markedly elevated in anti-HER2-resistant models, and its depletion sensitizes resistant cells to anti-HER2 therapy. To translate these findings therapeutically, we developed a potent and selective BRD8 PROTAC degrader with a DC50 of ∼100 nM. Combined treatment with the BRD8 degrader and anti-HER2 agents synergistically inhibits HR+/HER2+ breast cancer cell growth with superior efficacy and no detectable toxicity. Notably, the BRD8 degrader demonstrates fivefold greater potency than the BRD8 inhibitor DN02 across multiple HR+/HER2+ breast cancer cell lines. Finally, we developed a 3-gene BRD8 signature that predicts anti-HER2 therapy response in two independent clinical trials, establishing BRD8 as both a predictive biomarker and a central epigenetic regulator of therapeutic resistance. Our findings identify dual BRD8 and HER2 targeting as a promising precision medicine strategy for overcoming resistance in HR+/HER2+ breast cancer. Citation Format: Wei Xu, Ang Gao, Parth Khatri, Gui Ma, Huy Dinh, Charles Perou. BRD8 chromatin regulator mediates anti-HER2 response in HR+/HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 375.