@article{6d4e5197f8fb4395a1b3ea5914b10757,
title = "BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency",
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. Sun et al. show that inhibition of BRD4 induces homologous recombination deficiency, through depletion of CtBP, in cells across multiple tumor types and sensitizes them to PARP inhibition. Thus, inhibition of BRD4 reverses resistance to PARP inhibitors and expands the potential use of PARP inhibitors.",
keywords = "BRD4 inhibitor, CtBP-interacting protein, CtIP, PARP inhibitor, homologous recombination",
author = "Chaoyang Sun and Jun Yin and Yong Fang and Jian Chen and Jeong, {Kang Jin} and Xiaohua Chen and Vellano, {Christopher P.} and Zhenlin Ju and Wei Zhao and Dong Zhang and Yiling Lu and Funda Meric-Bernstam and Yap, {Timothy A.} and Maureen Hattersley and O'Connor, {Mark J.} and Huawei Chen and Stephen Fawell and Lin, {Shiaw Yih} and Guang Peng and Mills, {Gordon B.}",
note = "Funding Information: We thank Dr. Anirban Maitra for Pa01c, Pa02c, Pa03c, Pa04c, Pa09c, Pa16c, Pa18c, and Pa21c cells. We thank Drs. Helen Piwnica-Worms and Abena Redwood for WU-BC3 cell and a P53 knockdown variant. We thank Dr. Shunichi Takeda for DT40 and DT40 PARP1−/− cells. We thank Dr. Michael P. Kim for PATX53 PDX. This study is supported by a Susan G. Komen grant (SAC110052), a Stand Up to Cancer Dream Team Translational Research grant (SU2C-AACR-DT0209), a Breast Cancer Research Foundation grant (BCRF-17-108), an Ovarian Cancer Research Foundation grant (OCRF 545152), a Cancer Prevention & Research Institute of Texas grant (CPRIT RP170640), NIH grants 5U01CA168394, 5P50CA098258, and 5P50CA083639, a Cancer Center Support grant (CA016672), and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (all to G.B.M.). Funding Information: We thank Dr. Anirban Maitra for Pa01c, Pa02c, Pa03c, Pa04c, Pa09c, Pa16c, Pa18c, and Pa21c cells. We thank Drs. Helen Piwnica-Worms and Abena Redwood for WU-BC3 cell and a P53 knockdown variant. We thank Dr. Shunichi Takeda for DT40 and DT40 PARP1 −/− cells. We thank Dr. Michael P. Kim for PATX53 PDX. This study is supported by a Susan G. Komen grant ( SAC110052 ), a Stand Up to Cancer Dream Team Translational Research grant ( SU2C-AACR-DT0209 ), a Breast Cancer Research Foundation grant ( BCRF-17-108 ), an Ovarian Cancer Research Foundation grant ( OCRF 545152 ), a Cancer Prevention & Research Institute of Texas grant ( CPRIT RP170640 ), NIH grants 5U01CA168394 , 5P50CA098258 , and 5P50CA083639 , a Cancer Center Support grant ( CA016672 ), and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (all to G.B.M.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = mar,
day = "12",
doi = "10.1016/j.ccell.2018.01.019",
language = "English (US)",
volume = "33",
pages = "401--416.e8",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "3",
}