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

被引：224

作者：

Sun, Chaoyang ^{[1
,2
]}

Yin, Jun ^{[2
,3
]}

Fang, Yong ^{[1
,2
]}

Chen, Jian ^{[2
,4
]}

Jeong, Kang Jin ^{[2
]}

Chen, Xiaohua ^{[2
]}

Vellano, Christopher P. ^{[2
]}

Ju, Zhenlin ^{[5
]}

Zhao, Wei ^{[2
]}

Zhang, Dong ^{[2
]}

Lu, Yiling ^{[2
]}

Meric-Bernstam, Funda ^{[6
]}

Yap, Timothy A. ^{[6
]}

Hattersley, Maureen ^{[7
]}

O'Connor, Mark J. ^{[8
]}

Chen, Huawei ^{[7
]}

Fawell, Stephen ^{[7
]}

Lin, Shiaw-Yih ^{[2
]}

Peng, Guang ^{[9
]}

Mills, Gordon B. ^{[2
]}

机构：

[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Obstet & Gynecol, Wuhan 430030, Hubei, Peoples R China

[2] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[3] Aurora Res Inst, Milwaukee, WI 53202 USA

[4] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Gen Surg, Hangzhou 310000, Zhejiang, Peoples R China

[5] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA

[7] AstraZeneca, IMED Oncol, 35 Gatehouse Dr, Waltham, MA 02451 USA

[8] AstraZeneca, 1 Francis Crick Ave,Cambridge Biomed Campus, Cambridge CB2 0RE, England

[9] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA

来源：

CANCER CELL | 2018年 / 33卷 / 03期

关键词：

DNA-END RESECTION; OVARIAN-CANCER; BREAST-CANCER; SELECTIVE-INHIBITION; RESISTANCE; REPAIR; CELLS; THERAPY; RECRUITMENT; RUCAPARIB;

D O I：

10.1016/j.ccell.2018.01.019

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：401 / +

页数：24

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