Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition.


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.

  • 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
PubMed ID
Appears In
Sci Transl Med, 2017, 9 (400)