New Mouse Models Reveal CDK12's Role in Aggressive Ovarian Cancer Treatment

In a groundbreaking study published on June 11, 2025, researchers at the University of Michigan have developed a novel mouse model that mimics the aggressive characteristics of tubo-ovarian high-grade serous carcinoma (HGSC), the most prevalent and lethal form of ovarian cancer. This research highlights the role of the gene CDK12 as a tumor suppressor and reveals potential therapeutic strategies targeting CDK13 to combat this devastating disease.

Ovarian cancer ranks as the sixth leading cause of cancer deaths among women in the United States, with HGSC being responsible for a significant proportion of these fatalities. The disease is notorious for developing resistance to chemotherapy, emphasizing the urgent need for innovative treatment approaches. The newly engineered genetically modified mouse models (GEMMs) provide an essential platform for studying the disease, enabling researchers to investigate treatment responses in a system closely resembling human ovarian cancer.

According to Jean Ching-Yi Tian, the first author of the study, 'CDK12 is frequently mutated in human ovarian cancer, but its exact role wasn’t fully understood until now. We’ve shown that losing CDK12 function accelerates tumor progression in mice and creates a specific vulnerability that can be targeted with precision therapies.' This revelation is particularly significant given that CDK12 mutations occur in approximately 3% of tubo-ovarian HGSC cases.

The research team employed a CRISPR/Cas9-based synthetic lethality screen, identifying CDK13 as a critical gene in CDK12-deficient tumor cells. The findings indicate that tumors lacking CDK12 become reliant on CDK13 for survival, thus creating a therapeutic opportunity. 'When we inhibited CDK13, the cancer cells died,' Tian explained. 'This was a major insight into how we might exploit this vulnerability for treatment.'

To this end, the researchers tested a compound named YJ1206, which simultaneously targets both CDK12 and CDK13. In preclinical studies, this compound led to robust tumor cell death in CDK12-deficient cell lines and resulted in tumor shrinkage and increased immune cell infiltration in mouse models. These promising outcomes suggest the potential for combining CDK12/13 targeting with existing immune checkpoint inhibitors to enhance therapeutic efficacy.

The study also addresses the complex role of CDK12 in different cancers. While CDK12 acts as a tumor suppressor in ovarian cancer, it can exhibit oncogenic properties in other contexts, such as breast cancer. Tian noted, 'CDK12 is context-dependent; it can be amplified in some cancers and drive tumor growth. However, in ovarian and prostate cancers, it is often inactivated, leading to aggressive disease.'

The implications of this research extend into the realm of precision oncology. By sequencing ovarian tumors for CDK12 mutations, clinicians could identify patients who might benefit from CDK13-targeted therapies. 'CDK12 can serve as a biomarker,' Tian stated. 'If we can identify patients with CDK12 loss-of-function mutations, we can tailor treatments to achieve better outcomes.'

The findings from this study not only shed light on the biological mechanisms of ovarian cancer but also pave the way for developing targeted therapies that could significantly improve patient outcomes. As the research team prepares to advance these findings into clinical trials, the potential for better treatment strategies for ovarian cancer patients is on the horizon. 'We’re at an exciting moment,' Tian concluded. 'We’ve developed the models, identified the vulnerabilities, and demonstrated that the strategy works in mice. Now the next step is to move this into clinical development and help patients.'