Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance
Abstract 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, includi...
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| Language: | English |
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Springer Nature
2023-01-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202216235 |
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| author | Li‐Min Wang Pingyuan Wang Xiao‐Min Chen Hui Yang Shan‐Shan Song Zilan Song Li Jia Hua‐Dong Chen Xu‐Bin Bao Ne Guo Xia‐Juan Huan Yong Xi Yan‐Yan Shen Xin‐Ying Yang Yi Su Yi‐Ming Sun Ying‐Lei Gao Yi Chen Jian Ding Jing‐Yu Lang Ze‐Hong Miao Ao Zhang Jin‐Xue He |
| author_facet | Li‐Min Wang Pingyuan Wang Xiao‐Min Chen Hui Yang Shan‐Shan Song Zilan Song Li Jia Hua‐Dong Chen Xu‐Bin Bao Ne Guo Xia‐Juan Huan Yong Xi Yan‐Yan Shen Xin‐Ying Yang Yi Su Yi‐Ming Sun Ying‐Lei Gao Yi Chen Jian Ding Jing‐Yu Lang Ze‐Hong Miao Ao Zhang Jin‐Xue He |
| author_sort | Li‐Min Wang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-24325773452c46108ba801e5debd9f21 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-24325773452c46108ba801e5debd9f212025-08-24T11:43:13ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-01-0115312410.15252/emmm.202216235Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistanceLi‐Min Wang0Pingyuan Wang1Xiao‐Min Chen2Hui Yang3Shan‐Shan Song4Zilan Song5Li Jia6Hua‐Dong Chen7Xu‐Bin Bao8Ne Guo9Xia‐Juan Huan10Yong Xi11Yan‐Yan Shen12Xin‐Ying Yang13Yi Su14Yi‐Ming Sun15Ying‐Lei Gao16Yi Chen17Jian Ding18Jing‐Yu Lang19Ze‐Hong Miao20Ao Zhang21Jin‐Xue He22State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesUniversity of Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesPharm‐X Center, School of Pharmacy, Shanghai Jiao Tong UniversityState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesUniversity of Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of SciencesAbstract 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.https://doi.org/10.15252/emmm.202216235homologous recombination repairolaparib‐resistantPARP inhibitorPARP7type I interferons |
| spellingShingle | Li‐Min Wang Pingyuan Wang Xiao‐Min Chen Hui Yang Shan‐Shan Song Zilan Song Li Jia Hua‐Dong Chen Xu‐Bin Bao Ne Guo Xia‐Juan Huan Yong Xi Yan‐Yan Shen Xin‐Ying Yang Yi Su Yi‐Ming Sun Ying‐Lei Gao Yi Chen Jian Ding Jing‐Yu Lang Ze‐Hong Miao Ao Zhang Jin‐Xue He Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance EMBO Molecular Medicine homologous recombination repair olaparib‐resistant PARP inhibitor PARP7 type I interferons |
| title | Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance |
| title_full | Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance |
| title_fullStr | Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance |
| title_full_unstemmed | Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance |
| title_short | Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance |
| title_sort | thioparib inhibits homologous recombination repair activates the type i ifn response and overcomes olaparib resistance |
| topic | homologous recombination repair olaparib‐resistant PARP inhibitor PARP7 type I interferons |
| url | https://doi.org/10.15252/emmm.202216235 |
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