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Updated: Jan 17, 2026

Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
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BRD2 Upregulation as a Pan-Cancer Adaptive Resistance Mechanism to BET Inhibition

Suyakarn Archasappawat1,2, Juliette Jacques1, EunJung Lee1

  • 1Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, CA.

Biorxiv : the Preprint Server for Biology
|September 15, 2025
PubMed

Insights

Bromodomain and extraterminal motif (BET) inhibitors show promise in cancer treatment. Upregulation of BRD2 was identified as a mechanism of resistance to BET inhibitors, suggesting co-targeting BRD2 could improve cancer therapy efficacy.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Bromodomain and extraterminal motif (BET) inhibitors are emerging cancer therapeutics targeting epigenetic regulators like BRD4.
  • Resistance to BET inhibitors (BETi) is a significant challenge limiting their clinical efficacy.
  • Understanding adaptive resistance mechanisms is crucial for improving BETi-based cancer therapies.

Purpose of the Study:

  • To investigate the mechanisms of adaptive resistance to BET inhibitors in cancer.
  • To identify novel therapeutic targets for overcoming BETi resistance.
  • To explore the role of BRD2 in mediating resistance to BET inhibitors.

Main Methods:

  • Utilized cancer cell lines and *in vivo* tumor models.
  • Performed BRD2 knockdown and combined BRD2 depletion with JQ1 treatment.
  • Conducted BRD4 and BRD2 ChIP-seq analysis in pancreatic cancer cells.
  • Investigated the role of NFYA in regulating BRD2 expression.

Main Results:

  • BRD2 upregulation was identified as a conserved resistance mechanism to BET inhibition across multiple cancer types.
  • BRD2 knockdown sensitized cancer cells to BETi, and combined BRD2 depletion with JQ1 impaired tumor growth.
  • Resistant cells exhibited higher BRD2 chromatin occupancy compared to sensitive cells after BETi treatment.
  • NFYA was identified as a key mediator of BRD2 upregulation in response to BETi.

Conclusions:

  • BRD2 is a critical mediator of adaptive resistance to BET inhibitors in pan-cancer.
  • NFYA is a novel transcriptional regulator involved in BETi resistance.
  • Co-targeting BRD2 or its regulatory network presents a rational strategy to enhance the efficacy and durability of BET-based therapies.

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