Research ArticleCancer

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

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Science Translational Medicine  26 Jul 2017:
Vol. 9, Issue 400, eaal1645
DOI: 10.1126/scitranslmed.aal1645

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BET-ting on a new drug combination

PARP inhibitors are drugs that interfere with DNA repair, particularly in cancers with defects in homologous recombination. To identify drugs that may potentiate the activity of PARP inhibitors, Yang et al. performed a drug screen and discovered that BET inhibitors, a type of epigenetic regulators, act synergistically with PARP inhibitors. The authors found that BET inhibitors suppress homologous recombination, inducing the functional defect that sensitizes tumors to PARP inhibitors. The authors demonstrated the effectiveness of this combination approach in models of breast and ovarian cancer. They also provided genetic data showing that BET inhibitors may be able to target many other tumor types, suggesting that this combination treatment may have broad applicability.

Abstract

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 BRCA1 and RAD51, 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 BRD4 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.

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