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Cancer Cell. 2018 Mar 12;33(3):401-416.e8. doi: 10.1016/j.ccell.2018.01.019.

BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency.

Author information

1
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: suncydoctor@gmail.com.
2
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Aurora Research Institute, Milwaukee, WI 53202, USA.
3
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of General Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310000, China.
5
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
IMED Oncology, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA.
9
AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK.
10
Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein). Importantly, BRD4 inhibitor (BRD4i) treatment reversed multiple mechanisms of resistance to PARPi. Furthermore, PARPi and BRD4i are synergistic in multiple in vivo models.

KEYWORDS:

BRD4 inhibitor; CtBP-interacting protein; CtIP; PARP inhibitor; homologous recombination

PMID:
29533782
PMCID:
PMC5944839
DOI:
10.1016/j.ccell.2018.01.019
[Indexed for MEDLINE]
Free PMC Article

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