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

• 成果类型: Article
• 署名作者: Tien, Jean Ching-Yi; Zhai, Yali; Wu, Rong; Zhang, Yuping; Chang, Yu; Cheng, Yunhui; Todd, Abigail J.; Wheeler, Christina E.; Li, Shuqin; Mannan, Rahul; Cheng, Caleb; Magnuson, Brian; Cruz, Gabriel; Cao, Yizhi; Mahapatra, Somnath; Stolfi, Carmine; Cao, Xuhong; Su, Fengyun; Wang, Rui; Yang, Jianzhang; Zhou, Licheng; Qiao, Yuanyuan; Xiao, Lanbo; Cieslik, Marcin; Wang, Xiaoju; Wang, Zhen; Chou, Jonathan; Fearon, Eric R.; Ding, Ke; Cho, Kathleen R.; Chinnaiyan, Arul M.
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; University of Michigan System; University of Michigan; Howard Hughes Medical Institute; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9189
• DOI: 10.1073/pnas.2426909122
• 发表日期: 2025-06-12
• 关键词: expression; mutations; origin

摘要

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-sgPRNmodel). 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.