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

	Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer
	Ning Zhang 1; Yu-Nan Tian 1; Li-Na Zhou 1; Meng-Zhu Li 1; Hua-Dong Chen 1; Shan-Shan Song 1; Xia-Juan Huan 1; Xu-Bin Bao 1; Ao Zhang 1; Ze-Hong Miao 1
刊名	Cell Death & Disease
	2021
卷号	12 期号:2 页码:1
ISSN号	2041-4889
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 GSK3β 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 GSK3β 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 GSK3β 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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298619]
专题	中国科学院上海药物研究所
作者单位	1.Shanghai Institute of Materia Medica, Chinese Academy of Sciences 2.中国科学院大学
推荐引用方式 GB/T 7714	Ning Zhang,Yu-Nan Tian,Li-Na Zhou,et al. Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer[J]. Cell Death & Disease,2021,12(2):1.
APA	Ning Zhang.,Yu-Nan Tian.,Li-Na Zhou.,Meng-Zhu Li.,Hua-Dong Chen.,...&Jin-Xue He.(2021).Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer.Cell Death & Disease,12(2),1.
MLA	Ning Zhang,et al."Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer".Cell Death & Disease 12.2(2021):1.