What question did this study set out to answer?

To investigate how BET inhibition affects the FOXM1-MYC axis and its implications for PARP inhibitor response.

March 14, 2026npj Precision Oncology0 citationsOpen Access

BET inhibition disrupts the FOXM1-MYC axis to induce BRCAness and enhance PARP inhibitor response

PFPingping Fang ASAnais Saunders KMKay Minn

Key Points

To investigate how BET inhibition affects the FOXM1-MYC axis and its implications for PARP inhibitor response.
Conducted ENCODE analyses to determine co-occupancy of FOXM1 and MYC at DNA repair genes.
Performed transient knockdowns of FOXM1 and MYC to assess effects on BRCA1/RAD51 transcripts.
Used (+)-JQ1 and ZBC260 to inhibit BRD4 and evaluate effects on HR gene expression and cell viability.
Tested synergy between BET inhibition and PARP inhibitors in cancer cell assays.
BET inhibition with (+)-JQ1 reduced expression of HR genes like BRCA1 and RAD51.
BRD4 degradation enhanced PARP1 trapping and synergy with olaparib.
High BRD4 expression in ovarian cancer correlated with poor survival, suggesting it as a therapeutic target.

Abstract

Abstract Homologous recombination (HR) proficiency underlies intrinsic and acquired resistance to PARP inhibitors (PARPi). We identify a BRD4-dependent FOXM1-MYC transcriptional axis that sustains HR gene expression and limits PARPi response. ENCODE analyses revealed extensive co-occupancy of FOXM1 and MYC at regulatory regions of DNA repair genes, including BRCA1/2 and RAD51 paralogs, suggesting a shared HR program. Functionally, transient knockdown of FOXM1 or MYC reduced BRCA1/RAD51 transcripts, whereas sustained FOXM1 silencing triggered adaptive MYC upregulation that preserved HR output, indicating compensatory control. BET inhibition with (+)-JQ1 diminished FOXM1/MYC promoter occupancy at BRCA1 and RAD51, downregulated HR genes, and synergized with PARPi in viability and clonogenic assays. A BRD4 degrader (ZBC260) achieved potent BRD4 depletion at low nanomolar doses, suppressed FOXM1/MYC and HR gene expression, enhanced PARP1 trapping, and produced strong synergy with olaparib, including in patient-derived cancer cells. Clinically, BRD4 is highly expressed in ovarian cancer and independently predicts poor survival, outperforming FOXM1 and MYC. These data establish BRD4-directed disruption of the FOXM1–MYC axis as a strategy to induce “BRCAness” and broaden PARPi efficacy.

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