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

Author:

Wang Li‐Min12ORCID,Wang Pingyuan134,Chen Xiao‐Min25ORCID,Yang Hui12ORCID,Song Shan‐Shan12,Song Zilan3,Jia Li12,Chen Hua‐Dong12ORCID,Bao Xu‐Bin12,Guo Ne12ORCID,Huan Xia‐Juan12,Xi Yong12,Shen Yan‐Yan12,Yang Xin‐Ying12,Su Yi12,Sun Yi‐Ming12,Gao Ying‐Lei12,Chen Yi12,Ding Jian12,Lang Jing‐Yu25ORCID,Miao Ze‐Hong12ORCID,Zhang Ao123ORCID,He Jin‐Xue12ORCID

Affiliation:

1. State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China

2. University of Chinese Academy of Sciences Beijing China

3. Pharm‐X Center, School of Pharmacy Shanghai Jiao Tong University Shanghai China

4. Institute of Evolution and Marine Biodiversity Ocean University of China Qingdao China

5. The CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai China

Abstract

AbstractPoly‐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.

Funder

State Key Laboratory of Drug Research

National Natural Science Foundation of China

Science and Technology Commission of Shanghai Municipality

Publisher

Springer Science and Business Media LLC

Subject

Molecular Medicine

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