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

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BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency.
Cancer Cell ( IF 48.8 ) Pub Date : 2018-03-12 , DOI: 10.1016/j.ccell.2018.01.019
Chaoyang Sun ₁ , Jun Yin ₂ , Yong Fang ₁ , Jian Chen ₃ , Kang Jin Jeong ₄ , Xiaohua Chen ₄ , Christopher P Vellano ₄ , Zhenlin Ju ₅ , Wei Zhao ₄ , Dong Zhang ₄ , Yiling Lu ₄ , Funda Meric-Bernstam ₆ , Timothy A Yap ₆ , Maureen Hattersley ₇ , Mark J O'Connor ₈ , Huawei Chen ₇ , Stephen Fawell ₇ , Shiaw-Yih Lin ₄ , Guang Peng ₉ , Gordon B Mills ₄

Affiliation

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.
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Aurora Research Institute, Milwaukee, WI 53202, USA.
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.
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
IMED Oncology, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA.
AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK.
Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

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.

中文翻译：

BRD4 抑制与 PARP 抑制剂通过诱导同源重组缺陷产生合成致死作用。

聚（ADP-核糖）聚合酶抑制剂 (PARPi) 在由 BRCA1、BRCA2 和其他通路成员突变引起的同源重组 (HR) 缺陷 (HRD) 细胞中选择性发挥活性。我们寻找在 HR 感受态细胞中诱导 HRD 的小分子，以诱导 PARPi 的合成致死并扩展 PARPi 的效用。我们证明，通过消除 DNA 双链断裂切除蛋白 CtIP，抑制含溴结构域 4 (BRD4) 可诱导 HRD 并使多个肿瘤谱系的细胞对 PARPi 敏感，无论 BRCA1/2、TP53、RAS 或 BRAF 突变状态如何。 -末端结合蛋白相互作用蛋白）。重要的是，BRD4 抑制剂 (BRD4i) 治疗逆转了 PARPi 的多种耐药机制。此外，PARPi 和 BRD4i 在多种体内模型中具有协同作用。

更新日期：2018-03-13

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