Journal
CANCER RESEARCH
Volume 82, Issue 19, Pages 3588-3602Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-22-0222
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Funding
- National Natural Science Foundation of China [81922047, 82172596, 21837004, 32170755, 81974454, 82173077, 82173111]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB39050500]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20161313]
- Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
- Shanghai Municipal Key Clinical Specialty
- Shanghai Natural Science Foundation [20ZR1433100]
- Shanghai Collaborative Innovation Center for Translational Medicine [TM202004]
- Beijing Kuanghua Foundation for the Development of Chinese and Western Medicine (BKF) [KH-2021-LLZX-018]
- Shanghai Jiao Tong University School of Medicine [YG2021GD02, TMSK-2021-207]
- innovative research team of high-level local universities in Shanghai [SHSMU-ZLCX20210200]
- Shanghai Shenkang Hospital Development Center [SHDC2020CR3057B]
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This study develops a novel CDK12/CDK13 inhibitor that impairs both tumor and immune cells, showing potent anticancer activity in ovarian cancer.
Therapeutic perturbation of cyclin-dependent kinase 12 (CDK12) is proposed to have pleiotropic effects in ovarian cancer, including direct cytotoxicity against tumor cells and indirect induction of immunogenicity that confer synthetic sensitivity to immune-based treatment. However, formal testing of this hypothesis has been hindered by an insufficient mechanistic understanding of CDK12 and its close homolog CDK13, as well as generally unfavorable pharmacokinetics of available CDK12/ CDK13 covalent inhibitors. In this study, we used an innovative arsenous warhead modality to develop an orally bioavailable CDK12/CDK13 covalent compound. The dual CDK12/CDK13 inhibitors ZSQ836 exerted potent anticancer activity in cell culture and mouse models and induced transcriptional repro-gramming, including downregulation of DNA damage response genes. CDK12 and CDK13 were both ubiquitously expressed in primary and metastatic ovarian cancer, and the two kinases performed independent and synergistic functions to promote tumorigenicity. Unexpectedly, although ZSQ836 triggered geno-mic instability in malignant cells, it counterintuitively impaired lymphocytic infiltration in neoplastic lesions by interfering with T-cell proliferation and activation. These findings highlight the Janus-faced effects of dual CDK12/CDK13 inhibitors by simul-taneously suppressing tumor and immune cells, offering valuable insights into the future direction of drug discovery to pharma-cologically target CDK12.Significance: This study dissects the specific roles of CDK12 and CDK13 in ovarian cancer and develops a CDK12/CDK13 inhibitor that impairs both tumor and immune cells, which could guide future CDK12 inhibitor development.
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