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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE307284 | GEO | 2026/04/29

REPOSITORIES: GEO

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Project description:Targeting the epigenome to modulate gene expression programs driving cancer development has emerged as an exciting avenue for therapeutic intervention. Pharmacological inhibition of the bromodomain and extraterminal (BET) family of chromatin adapter proteins has proven effective in this regard, suppressing growth of diverse cancer types mainly through downregulation of the c-MYC oncogene and its downstream transcriptional program. While initially effective, resistance to BET inhibitors (BETi) typically occurs through mechanisms that reactivate MYC expression. We have previously shown that lung adenocarcinoma (LAC) is inhibited by JQ1 through suppression of FOSL1, suggesting that the epigenetic landscape of tumor cells from different origins and differentiation states influences BETi response. Here, we assessed how these differences affect mechanisms of BETi resistance through the establishment of isogenic pairs of JQ1 sensitive and resistant LAC cell lines. We found that resistance to JQ1 in LAC occurs independent of FOSL1 while MYC levels remain unchanged between resistant cells and their JQ1 treated parental counterparts. Furthermore, while epithelial-mesenchymal transition (EMT) is observed upon resistance, TGF- induced EMT did not confer resistance in JQ1 sensitive LAC lines, suggesting this is a consequence, rather than a driver of BETi resistance in our model systems. Importantly, siRNA knockdown demonstrated that JQ1 resistant cell lines are still dependent on BRD4 expression and we found that phosphorylation of BRD4 is elevated in resistant LACs, identifying casein kinase 2 (CK2) as a candidate protein mediating this effect. Inhibition of CK2, as well as downstream transcriptional targets of phosphorylated BRD4 - including AXL and activators of the PI3K pathway - synergize with JQ1 to inhibit BETi resistant LAC. Overall, this demonstrates that the mechanism of resistance to BETi varies depending on cancer type, with LAC cells developing JQ1 resistance independent of MYC re-activation, and identifying CK2 phosphorylation of BRD4 as a potential target to overcome resistance in this cancer.

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

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