Research conducted at the University of Michigan Rogel Cancer Center has led to the identification of a new subtype of aggressive prostate cancer. In two recently published papers in Cell Reports Medicine, researchers explore how alterations in the CDK12 gene drive prostate cancer development and present a promising degrader that targets CDK12 and a related gene to destroy tumors. The loss of the CDK12 gene was found in approximately 7% of patients with metastatic prostate cancer, indicating a potential link to a more aggressive form of the disease. CDK12 is also implicated in ovarian cancers.
To understand the impact of CDK12 loss on a molecular level, researchers created a mouse model that mirrored the genetic alterations observed in human prostate cancers. When CDK12 loss was induced in mouse prostates, precursor lesions formed, and the addition of loss of the p53 oncogene led to the development of invasive prostate cancer. The mouse model provided insights into the mechanism by which CDK12 loss induces DNA damage, activating other known cancer driver genes and causing rapid DNA replication, ultimately resulting in DNA damage. These findings have added to the understanding of how CDK12 loss drives prostate cancer.
Furthermore, researchers identified the significance of a partner gene, CDK13, in targeting the genetic alteration therapeutically. They developed a potential therapy designed to degrade both CDK12 and CDK13, which showed promising results in cell lines and mice. The degrader specifically bound to these genes and halted the growth of cancer cells without affecting normal cells. Additionally, knocking down CDK12/13 activated the AKT pathway, which is involved in cancer development. Combining the CDK12/13 degrader with existing therapies targeting AKT displayed a synergistic effect in destroying cancer cells, highlighting the potential for combination therapies.
The ability of the CDK12/13 degrader to be absorbed orally presents a significant advantage, as most protein degraders are too large to be taken orally, limiting their potential in drug development. The team’s collaborative effort with medicinal chemist Ke Ding from the Shanghai Institute of Chemistry was instrumental in developing orally bioavailable CDK12/13 degraders. By combining a CDK12/13 degrader with other approved therapies, researchers aim to prevent the development of resistance mechanisms that often hinder single-agent cancer treatments. The study emphasizes the importance of finding the right combination of therapies to improve treatment outcomes for cancer patients.
The findings from these studies have significant implications for future research and potential clinical applications. Researchers intend to further develop the CDK12/13 degrader with the goal of advancing it to a clinical trial. By understanding the mechanisms by which CDK12 loss drives prostate cancer and identifying therapeutic targets, this research has opened up new possibilities for the treatment of aggressive prostate cancer and potentially other cancers where CDK12 plays a role. The multidisciplinary approach taken by the research team demonstrates the importance of collaborations in advancing cancer research and developing innovative therapeutic strategies.