2. Academic Validation
  3. Defining CDK12 as a tumor suppressor and therapeutic target in mouse models of tubo-ovarian high-grade serous carcinoma

Defining CDK12 as a tumor suppressor and therapeutic target in mouse models of tubo-ovarian high-grade serous carcinoma

  • Proc Natl Acad Sci U S A. 2025 Jun 17;122(24):e2426909122. doi: 10.1073/pnas.2426909122.
Jean Ching-Yi Tien 1 2,  Yali Zhai 2,  Rong Wu 2,  Yuping Zhang 1 2,  Yu Chang 1 2,  Yunhui Cheng 1 2,  Abigail J Todd 1 2,  Christina E Wheeler 1 2,  Shuqin Li 1 2,  Rahul Mannan 1 2,  Caleb Cheng 1 2,  Brian Magnuson 1 2,  Gabriel Cruz 1 2,  Yizhi Cao 1 2,  Somnath Mahapatra 1 2,  Carmine Stolfi 3,  Xuhong Cao 1 2,  Fengyun Su 1 2,  Rui Wang 1 2,  Jianzhang Yang 4,  Licheng Zhou 4,  Yuanyuan Qiao 1 2 5,  Lanbo Xiao 1 2,  Marcin Cieslik 1 2 6,  Xiaoju Wang 1 2,  Zhen Wang 4,  Jonathan Chou 7 8,  Eric R Fearon 2 3 5 9,  Ke Ding 4,  Kathleen R Cho 2 5,  Arul M Chinnaiyan 1 2 5 10 11
Affiliations

Affiliations

  • 1 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
  • 2 Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
  • 3 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China.
  • 5 Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109.
  • 6 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
  • 7 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115.
  • 8 Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA 94115.
  • 9 Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109.
  • 10 HHMI, University of Michigan, Ann Arbor, MI 48109.
  • 11 Department of Urology, University of Michigan, Ann Arbor, MI 48109.
PMID: 40504161 DOI: 10.1073/pnas.2426909122
Abstract

Ovarian Cancer is the sixth leading cause of Cancer death among American women, with most fatalities attributable to tubo-ovarian high-grade serous carcinoma (HGSC). This malignancy usually develops resistance to conventional chemotherapy, underscoring the need for robust preclinical models to guide the development of novel therapies. Here, we introduce an HGSC mouse model generated via Ovgp1-driven Cre recombinase effecting CRISPR/Cas9-mediated deletion of Trp53, Rb1, and Nf1 tumor suppressors in mouse oviductal epithelium (m-sgPRN model). Cyclin-dependent kinase 12 (CDK12) inactivation-frequently observed in human HGSC-is associated with poorer outcomes, DNA damage accumulation (including tandem duplications), and increased tumor immunogenicity. In our system, coablation of CDK12 (m-sgPRN;Cdk12KO) recapitulated hallmark features of HGSC, while accelerating tumor progression and reducing survival. In a conventional (Cre-lox-mediated) Trp53/Nf1/Rb1 triple knockout model with concurrent CDK12 ablation (PRN;Cdk12KO mice), we observed T cell-rich immune infiltrates mirroring those seen clinically. We established both models as subcutaneous or intraperitoneal syngeneic allografts of CDK12-inactivated HGSC that exhibited sensitivity to immune checkpoint blockade. Furthermore, a CRISPR/Cas9 synthetic lethality screen in PRN;Cdk12KO-derived cell lines identified CDK13-an essential paralog of CDK12-as the most depleted candidate, confirming a previously reported synthetic lethal interaction. Pharmacologic CDK13/12 degradation (employing YJ1206) demonstrated enhanced efficacy in cell lines derived from both m-sgPRN;Cdk12KO and PRN;Cdk12KO models. Our results define CDK12 as a key tumor suppressor in tubo-ovarian HGSC and highlight CDK13 targeting as a promising therapeutic approach in CDK12-inactive disease. Additionally, we have established valuable in vivo resources to facilitate further investigation and drug development in this challenging malignancy.

Keywords

CDK12; CDK12/13 degrader; genetically engineered mouse models (GEMMs); ovarian cancer.

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