BRD2 upregulation as a pan-cancer adaptive resistance mechanism to BET inhibition [ChIP-seq]

Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are promising cancer therapeutics that target epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors (BETi) limits their clinical utility, necessitating a better understanding of adaptive mechanisms. We identified BRD2 upregulation as a conserved response to BET inhibition across multiple cancer types and hypothesized that BRD2 compensates for BRD4 loss, sustaining essential transcriptional programs during treatment. Consistent with this, BRD2 knockdown sensitized cancer cells to BETi in vitro, and combining BRD2 depletion and JQ1 treatment significantly impaired tumor growth in vivo. At the chromatin level, BRD2 and BRD4 ChIP-seq analysis of pancreatic cancer cells showed consistent BRD4 loss from chromatin after JQ1 treatment, while BRD2 displacement differed by sensitivity. Resistant cells maintained higher BRD2 occupancy than sensitive cells, suggesting a link between BRD2 retention and drug response. To dissect the underlying mechanism of BRD2 upregulation upon BET inhibition, we analyzed co-expression networks and observed that NFYA is co-expressed with BRD2 across diverse tissues and cancer types. Consistently, NFYA binds the BRD2 promoter. NFYA depletion abrogated BRD2 upregulation upon BETi treatment, indicating that NFYA is required for BRD2 induction following BET inhibition. Collectively, our findings establish BRD2 as a critical mediator of adaptive resistance to BETi in pan-cancer and identify NFYA as a novel transcriptional regulator of this process. Co-targeting BRD2 or its regulatory network offers a rational strategy to enhance the durability and efficacy of BET-based therapies.