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

• Published in: Science translational medicine Vol. 9; no. 400
• Main Authors: Yang, Lu, Zhang, Youyou, Shan, Weiwei, Hu, Zhongyi, Yuan, Jiao, Pi, Jingjiang, Wang, Yueying, Fan, Lingling, Tang, Zhaoqing, Li, Chunsheng, Hu, Xiaowen, Tanyi, Janos L, Fan, Yi, Huang, Qihong, Montone, Kathleen, Dang, Chi V, Zhang, Lin
• Format: Journal Article
• Language: English
• Published: United States 26.07.2017
• Subjects: Acetanilides - therapeutic use; Animals; Antineoplastic Agents - therapeutic use; Azepines - therapeutic use; Benzodiazepines - therapeutic use; Breast Neoplasms - drug therapy; Cell Line, Tumor; DNA Damage - drug effects; DNA Damage - genetics; Drug Synergism; Female; Heterocyclic Compounds, 3-Ring - therapeutic use; Homologous Recombination - drug effects; Homologous Recombination - genetics; Humans; Ovarian Neoplasms - drug therapy; Phthalazines - therapeutic use; Piperazines - therapeutic use; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Triazoles - therapeutic use
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aal1645

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 and , 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 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.