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Sci Transl Med. 2017 Jul 26;9(400). pii: eaal1645. doi: 10.1126/scitranslmed.aal1645.

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

Author information

1
Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Obstetrics and Gynecology, West China Medical School, Sichuan University, Chengdu 610041, China.
3
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
4
Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Wistar Institute, Philadelphia, PA 19104, USA.
7
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
9
Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA 19104, USA. linzhang@mail.med.upenn.edu.

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.

PMID:
28747513
PMCID:
PMC5705017
DOI:
10.1126/scitranslmed.aal1645
[Indexed for MEDLINE]
Free PMC Article

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