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Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance

文献类型：期刊论文

作者Wang, Li-Min1,2; Wang, Pingyuan1,3,4; Chen, Xiao-Min2,5; Yang, Hui1,2; Song, Shan-Shan1,2; Song, Zilan3; Jia, Li1,2; Chen, Hua-Dong1,2; Bao, Xu-Bin1,2; Guo, Ne1,2
刊名EMBO MOLECULAR MEDICINE
出版日期2023-01-18
页码24
ISSN号1757-4676
关键词homologous recombination repair olaparib-resistant PARP inhibitor PARP7 type I interferons
DOI10.15252/emmm.202216235
通讯作者Lang, Jing-Yu(jylang@sibs.ac.cn) ; Miao, Ze-Hong(zhmiao@simm.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn) ; He, Jin-Xue(jinxue_he@simm.ac.cn)
英文摘要Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here, we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1-dependent DNA damage and replication stress, causing S-phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR-mediated DNA repair while increasing RAD51 foci formation. Notably, the on-target inhibition of PARP7 by thioparib-activated STING/TBK1-dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome-scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next-generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier-generation PARPi.
WOS关键词RIBOSE POLYMERASE INHIBITORS ; PARP INHIBITORS ; DNA-DAMAGE ; SYNTHETIC LETHALITY ; ANTICANCER ACTIVITY ; CANCER-CELLS ; LEUKEMIA ; DEFICIENCY ; BIOMARKERS ; MUTATIONS
资助项目National Natural Science Foundation of China[82073875] ; National Natural Science Foundation of China[81773764] ; National Natural Science Foundation of China[82073865] ; Strategic Priority Research Program of the Chinese Academy of Sciences[29201731121100101] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12010306] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020104] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020109] ; Strategic Priority Research Program of the Chinese Academy of Sciences[CASIMM0120185003] ; Science and Technology Commission of Shanghai Municipality (Shanghai Rising-Star Program)[19QA1410900] ; State Key Laboratory of Drug Research ; SA-SIBS Scholarship Program
WOS研究方向Research & Experimental Medicine
语种英语
出版者WILEY
WOS记录号WOS:000916493100001
源URL[http://119.78.100.183/handle/2S10ELR8/303531]  
专题新药研究国家重点实验室
通讯作者Lang, Jing-Yu; Miao, Ze-Hong; Zhang, Ao; He, Jin-Xue
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Shanghai Jiao Tong Univ, Pharm Ctr 10, Sch Pharm, Shanghai, Peoples R China
4.Ocean Univ China, Inst Evolut & Marine Biodivers, Qingdao, Peoples R China
5.Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Chinese Acad Sci, CAS Key Lab Tissue Microenvironm & Tumor, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Li-Min,Wang, Pingyuan,Chen, Xiao-Min,et al. Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance[J]. EMBO MOLECULAR MEDICINE,2023:24.
APA Wang, Li-Min.,Wang, Pingyuan.,Chen, Xiao-Min.,Yang, Hui.,Song, Shan-Shan.,...&He, Jin-Xue.(2023).Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance.EMBO MOLECULAR MEDICINE,24.
MLA Wang, Li-Min,et al."Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance".EMBO MOLECULAR MEDICINE (2023):24.

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来源：上海药物研究所

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