Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition.
Abstact
Strategies to enhance response to poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)-proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells. We also found that inhibition or depletion of BET proteins impairs transcription of <i>BRCA1</i> and <i>RAD51</i>, two genes essential for HR. Moreover, BETi treatment sensitized tumors to PARP inhibition in preclinical animal models of HR-proficient breast and ovarian cancers. Finally, we showed that the <i>BRD4</i> gene was focally amplified across 20 types of common cancers. Combination with BETi could greatly expand the utility of PARP inhibition to patients with HR-proficient cancer.
Authors
- Dang CV
- Fan L
- Fan Y
- Hu X
- Hu Z
- Huang Q
- Li C
- Montone K
- Pi J
- Shan W
- Tang Z
- Tanyi JL
- Wang Y
- Yang L
- Yuan J
- Zhang L
- Zhang Y