Abstract 6806: Deciphering the role of BRD2 in acute adaptive response to BET inhibitors across cancers

Abstract Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are a promising therapeutic strategy against cancer, targeting key epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors poses a significant challenge, necessitating a deeper understanding of adaptive mechanisms. Here, we identified the upregulation of BRD2, another member of the BET protein family, as a conserved response to BET inhibition across multiple cancer types. We hypothesize that this upregulation facilitates cellular adaptation to treatment, reducing drug efficacy and potentially contributing to resistance over time. To test this, we performed BRD2 knockdown, demonstrating that BRD2 depletion sensitizes pancreatic cancer cells to BET inhibitors in vitro. Furthermore, a combination of BRD2 knockdown with JQ1 treatment significantly impaired tumor growth in vivo. Mechanistically, ChIP-seq analysis of BRD2 and BRD4 occupancy upon JQ1 treatment revealed that BRD2 and BRD4 share common binding sites. JQ1 caused a substantial loss of BRD4 from chromatin, while BRD2 was modestly affected. Although JQ1 has a higher affinity for BRD4 than for BRD2, our data suggest that higher cellular abundance of BRD2 compensates for BRD4 function under BET inhibitor treatment, thereby contributing to adaptive resistance and sustaining essential transcriptional programs. These findings highlight BRD2 as a key player in the adaptive response to BET inhibition and a potential therapeutic target to enhance the efficacy of BET inhibitors in pancreatic cancer and other malignancies. Citation Format: Suyakarn Archasappawat, Eunjung Lee, Chang-il Hwang. Deciphering the role of BRD2 in acute adaptive response to BET inhibitors across cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6806.