Glycogen synthase kinase 3 beta inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer

doi:10.1038/s41419-021-03475-4

	Glycogen synthase kinase 3 beta inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer
	Zhang, Ning 1,2; Tian, Yu-Nan 1,2; Zhou, Li-Na 1,2; Li, Meng-Zhu 1,2; Chen, Hua-Dong 1,2; Song, Shan-Shan 1,2; Huan, Xia-Juan 1,2; Bao, Xu-Bin 1,2; Zhang, Ao 3; Miao, Ze-Hong 1,2
刊名	CELL DEATH & DISEASE
	2021-02-15
卷号	12 期号:2 页码:18
ISSN号	2041-4889
DOI	10.1038/s41419-021-03475-4
通讯作者	Miao, Ze-Hong(zhmiao@simm.ac.cn) ; He, Jin-Xue(jinxue_he@simm.ac.cn)
英文摘要	Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (<= 60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. The combination of GSK3 beta and PARP inhibition causes replication stress and DNA double-strand breaks, resulting in increased anaphase bridges and abnormal spindles. Mechanistically, inhibition or genetic depletion of GSK3 beta was found to impair the HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3 beta could enhance the in vivo sensitivity to simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.
资助项目	National Natural Science Foundation of China[81773764] ; National Natural Science Foundation of China[82073875] ; National Natural Science Foundation of China[82073865] ; Chinese Academy of Sciences[29201731121100101] ; Chinese Academy of Sciences[XDA12020104] ; Chinese Academy of Sciences[XDA12020109] ; Chinese Academy of Sciences[CASIMM0120185003] ; Science and Technology Commission of Shanghai Municipality[19QA1410900] ; State Key Laboratory of Drug Research ; SA-SIBS Scholarship Program
WOS研究方向	Cell Biology
语种	英语
出版者	SPRINGERNATURE
WOS记录号	WOS:000620643500006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295781]
专题	中国科学院上海药物研究所
通讯作者	Miao, Ze-Hong; He, Jin-Xue
作者单位	1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Ning,Tian, Yu-Nan,Zhou, Li-Na,et al. Glycogen synthase kinase 3 beta inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer[J]. CELL DEATH & DISEASE,2021,12(2):18.
APA	Zhang, Ning.,Tian, Yu-Nan.,Zhou, Li-Na.,Li, Meng-Zhu.,Chen, Hua-Dong.,...&He, Jin-Xue.(2021).Glycogen synthase kinase 3 beta inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer.CELL DEATH & DISEASE,12(2),18.
MLA	Zhang, Ning,et al."Glycogen synthase kinase 3 beta inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer".CELL DEATH & DISEASE 12.2(2021):18.