| Literature DB >> 29533782 |
Chaoyang Sun1, Jun Yin2, Yong Fang3, Jian Chen4, Kang Jin Jeong5, Xiaohua Chen5, Christopher P Vellano5, Zhenlin Ju6, Wei Zhao5, Dong Zhang5, Yiling Lu5, Funda Meric-Bernstam7, Timothy A Yap7, Maureen Hattersley8, Mark J O'Connor9, Huawei Chen8, Stephen Fawell8, Shiaw-Yih Lin5, Guang Peng10, Gordon B Mills5.
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.Entities:
Keywords: BRD4 inhibitor; CtBP-interacting protein; CtIP; PARP inhibitor; homologous recombination
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Year: 2018 PMID： 29533782 PMCID： PMC5944839 DOI： 10.1016/j.ccell.2018.01.019
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743