BET inhibition disrupts the FOXM1-MYC axis to induce BRCAness and enhance PARP inhibitor response - PubMed
5 hours ago
- #BRCAness
- #BET inhibition
- #PARP inhibitor
- BET inhibition disrupts the FOXM1-MYC axis to induce BRCAness and enhance PARP inhibitor response.
- HR proficiency underlies resistance to PARP inhibitors (PARPi).
- A BRD4-dependent FOXM1-MYC transcriptional axis sustains HR gene expression and limits PARPi response.
- FOXM1 and MYC co-occupy regulatory regions of DNA repair genes, including BRCA1/2 and RAD51 paralogs.
- Transient knockdown of FOXM1 or MYC reduces BRCA1/RAD51 transcripts.
- Sustained FOXM1 silencing triggers adaptive MYC upregulation, preserving HR output.
- BET inhibition with (+)-JQ1 diminishes FOXM1/MYC promoter occupancy at BRCA1 and RAD51, downregulates HR genes, and synergizes with PARPi.
- BRD4 degrader (ZBC260) suppresses FOXM1/MYC and HR gene expression, enhances PARP1 trapping, and synergizes with olaparib.
- BRD4 is highly expressed in ovarian cancer and predicts poor survival, outperforming FOXM1 and MYC.
- BRD4-directed disruption of the FOXM1-MYC axis induces 'BRCAness' and broadens PARPi efficacy.