combining53bp1withbrca1asabiomarkertopredictthesensitivityofpolyadpribosepolymeraseparpinhibitors

doi:10.1038/aps.2017.8

	combining53bp1withbrca1asabiomarkertopredictthesensitivityofpolyadpribosepolymeraseparpinhibitors
	Yang Zhongmin 1; Liao Xuemei 2; Chen Yi 2; Shen Yanyan 2; Yang Xinying 2; Su Yi 2; Sun Yiming 2; Gao Yinglei 2; Ding Jian 2; Zhang Ao 2
刊名	actapharmacologicasinica
	2017
卷号	38 期号:7 页码:1036
关键词	homologous recombination repair defects breast cancer ovarian cancer TALEN combined biomarker simmiparib olaparib
ISSN号	1671-4083
DOI	10.1038/aps.2017.8
英文摘要	Over half of patients with BRCAl-deficient cancers do not respond to treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we report that a combination of 53BP1 and BRCA1 may serve as a biomarker of PARP inhibitor sensitivity. Based on the mRNA levels of four homologous recombination repair (HR) genes and PARP inhibitor sensitivity, we selected BRCAl-deficient MDA-MB-436 cells to conduct RNA interference. Reducing expression of 53BP1, but not the other three HR genes, was found to lower simmiparib sensitivity. Additionally, we generated 53BP1~(-1-)/BRCA1~(-/-) clonal variants by the transcription activator-like effector nuclease (TALEN) technique and found that depleting 53BP1 impaired PARP inhibitor sensitivity with a 36.7-fold increase in their IC_(50) values. Consistent with its effect on PARP inhibitor sensitivity, 53BP1 loss alleviated cell cycle arrest and apoptosis and partially restored HR function. Importantly, 53BP1 depletion dramatically reduced the ability of PARP inhibitors to suppress tumor growth in vivo. The inhibition rate of simmiparib was 74.16% for BRCAl-deficient MDA-MB-436 xenografts, but only 7.79% for 53BP1/BRCA1-deficient xenografts. Re-expressing 53BP1 in the dual-deficient cells restored PARP inhibitor sensitivity and the levels of HR regulators. Considering that at least 10% of BRCAl-deficient breast and ovarian cancers have reduced expression of 53BP1, using a combination of 53BP1 with BRCA1 as a biomarker for patient selection should reduce the number of patients undergoing futile treatment with PARP inhibitors.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/287971]
专题	中国科学院上海药物研究所
作者单位	1.南昌大学 2.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Yang Zhongmin,Liao Xuemei,Chen Yi,et al. combining53bp1withbrca1asabiomarkertopredictthesensitivityofpolyadpribosepolymeraseparpinhibitors[J]. actapharmacologicasinica,2017,38(7):1036.
APA	Yang Zhongmin.,Liao Xuemei.,Chen Yi.,Shen Yanyan.,Yang Xinying.,...&Miao Zehong.(2017).combining53bp1withbrca1asabiomarkertopredictthesensitivityofpolyadpribosepolymeraseparpinhibitors.actapharmacologicasinica,38(7),1036.
MLA	Yang Zhongmin,et al."combining53bp1withbrca1asabiomarkertopredictthesensitivityofpolyadpribosepolymeraseparpinhibitors".actapharmacologicasinica 38.7(2017):1036.