BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer.
BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer.
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DOI：
10.1016/j.celrep.2017.11.095
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发表时间：
2017-12-19
期刊：
影响因子：
8.8
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Karakashev S;Zhu H;Yokoyama Y;Zhao B;Fatkhutdinov N;Kossenkov AV;Wilson AJ;Simpkins F;Speicher D;Khabele D;Bitler BG;Zhang R
已知PARP抑制是BRCA突变型癌症中的有效临床策略，但PARP抑制尚未应用于BRCA活性肿瘤。在这里，我们显示了BET布罗莫结构域抑制与PARP抑制在BRCA-熟练的卵巢癌中由于有丝分裂灾难的协同作用。用BET抑制剂JQ 1处理BRCA-熟练卵巢癌细胞，下调G2-M细胞周期检查点调节因子WEE 1和DNA损伤反应因子TOPBP 1。当与PARP抑制剂Olaparib联合使用时，我们观察到DNA损伤和检查点缺陷的协同增加，尽管DNA损伤累积，但这允许细胞进入有丝分裂，最终导致有丝分裂灾难。此外，JQ 1和奥拉帕尼在异种移植卵巢癌小鼠模型中显示出对BRCA-活性癌症的体内生长的协同抑制。我们的研究结果表明，BET抑制剂和PARP抑制剂的组合代表了BRCA-活性癌症的潜在治疗策略。Karakashev等人显示了BET溴结构域抑制与PARP抑制在BRCA有效卵巢癌中的协同作用。这种抑制剂的组合可以协同增加DNA损伤和细胞周期检查点缺陷，这允许细胞进入有丝分裂，尽管DNA损伤积累，最终导致有丝分裂灾难。
PARP inhibition is known to be an effective clinical strategy in BRCA-mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here we show synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell cycle checkpoint regulator WEE1 and the DNA damage response factor TOPBP1. When combined with the PARP inhibitor Olaparib, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers. Karakashev et al. show synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers. This combination of inhibitors can synergistically increase DNA damage and cell cycle checkpoint defects, which allows cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe.
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10.1083/jcb.201608026
发表时间：
2016-11-07
期刊：
The Journal of cell biology
影响因子：
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作者：
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