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Combining 53BP1 with BRCA1 as a biomarker to predict the sensitivity of poly(ADP-ribose) polymerase (PARP) inhibitors

文献类型：期刊论文

作者Yang, Zhong-min1,2,3; Liao, Xue-mei2,3; Chen, Yi2,3; Shen, Yan-yan2,3; Yang, Xin-ying2,3; Su, Yi2,3; Sun, Yi-ming2,3; Gao, Ying-lei2,3; Ding, Jian2,3; Zhang, Ao4
刊名ACTA PHARMACOLOGICA SINICA
出版日期2017-07
卷号38期号:7页码:1038-1047
关键词homologous recombination repair defects breast cancer ovarian cancer TALEN combined biomarker simmiparib olaparib
ISSN号1671-4083
DOI10.1038/aps.2017.8
文献子类Article
英文摘要Over half of patients with BRCA1-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 BRCA1-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(-/-)/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 IC50 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 BRCA1-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 BRCA1-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.
WOS关键词ANTICANCER ACTIVITY ; BREAST-CANCER ; CELLS ; RESISTANCE ; EXPRESSION ; TUMORS
资助项目National Natural Science Foundation of China[81573450] ; National Natural Science Foundation of China[81373446] ; National Natural Science Foundation of China[81321092] ; National Natural Science Foundation of China[81603160] ; National Natural Science Foundation of China[81402961] ; Chinese Academy of Sciences[XDA12020104] ; Chinese Academy of Sciences[XDA12020205] ; Chinese Academy of Sciences[CASIMM0120152003] ; Chinese Academy of Sciences[CASIMM-0120153005] ; Science and Technology Commission of Shanghai Municipality[16JC1406300] ; State Key Laboratory of Drug Research[SIMM1601ZZ-03]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000404918600007
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/272586]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者He, Jin-xue; Miao, Ze-hong
作者单位1.Nanchang Univ, Coll Pharm, Nanchang 330006, Jiangxi, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Zhong-min,Liao, Xue-mei,Chen, Yi,et al. Combining 53BP1 with BRCA1 as a biomarker to predict the sensitivity of poly(ADP-ribose) polymerase (PARP) inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2017,38(7):1038-1047.
APA Yang, Zhong-min.,Liao, Xue-mei.,Chen, Yi.,Shen, Yan-yan.,Yang, Xin-ying.,...&Miao, Ze-hong.(2017).Combining 53BP1 with BRCA1 as a biomarker to predict the sensitivity of poly(ADP-ribose) polymerase (PARP) inhibitors.ACTA PHARMACOLOGICA SINICA,38(7),1038-1047.
MLA Yang, Zhong-min,et al."Combining 53BP1 with BRCA1 as a biomarker to predict the sensitivity of poly(ADP-ribose) polymerase (PARP) inhibitors".ACTA PHARMACOLOGICA SINICA 38.7(2017):1038-1047.

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来源：上海药物研究所

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