Researchers have explored how changes in the CDK12 gene contribute to the development of prostate cancer and have proposed a promising new drug that targets CDK12 along with a related gene to help eliminate tumors.
When a team from the University of Michigan Rogel Cancer Center discovered a new type of aggressive prostate cancer, they recognized the need to delve into how these genetic changes were fueling the disease and to find effective treatment options.
In two recent studies published in Cell Reports Medicine, they detail how variations in the CDK12 gene lead to the progression of prostate cancer. They also report on a potential drug that targets CDK12 and a related gene to attack tumors.
It was previously observed that about 7% of patients with metastatic prostate cancer had lost the CDK12 gene, indicating that this loss might be associated with a more aggressive version of the cancer. This conclusion was drawn from analysis of DNA and RNA in patient tumor samples. The CDK12 gene is also implicated in some cases of ovarian cancer.
To further investigate the molecular effects of losing CDK12, researchers developed a mouse model that simulates the genetic changes seen in human prostate cancers.
“We were surprised to find that inducing CDK12 loss in mouse prostates led to the formation of precursor lesions. When we also knocked out the p53 oncogene, the mice developed actual invasive prostate cancer,” noted Arul M. Chinnaiyan, M.D., Ph.D., the senior author and director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine. “Having a genetically engineered mouse model that reflects what we observe in human prostate cancer is a valuable addition to the field.”
Using this mouse model, the researchers identified the mechanism by which the loss of CDK12 causes DNA damage. The absence of CDK12 was found to activate other cancer-driving genes, leading to their overexpression and a rapid replication of DNA. The interaction of these processes results in DNA damage.
“These simultaneous studies are quite significant. We established an animal model and elucidated how CDK12 loss drives prostate cancer,” Chinnaiyan said.
The research team also found that another gene, CDK13, plays a crucial role in targeted therapy for this alteration. They developed a potential treatment aimed at degrading both CDK12 and CDK13. Tests on cell cultures and mice demonstrated that the degrader selectively binds to CDK12 and CDK13, inhibiting cancer cell growth more effectively than in normal cells. Furthermore, this degrader can be taken orally, offering an advantage as many protein degraders are too large for oral absorption, which has restricted their usage in drug development.
Additionally, they discovered that reducing levels of CDK12/13 activates the AKT pathway, which is involved in cancer progression. When this CDK12/13 degrader was combined with existing AKT-targeting therapies, there was a synergistic effect that enhanced the destruction of cancer cells. This indicates the potential for pairing the CDK12/13 degrader with other approved treatments.
“It is widely recognized that relying on single therapies for cancer can be difficult. Patients often develop resistance. If we can successfully identify the right combinations, we may be able to prevent these resistance mechanisms. This is one of the advantages of finding FDA-approved agents to use with CDK12/13 degraders,” explained Chinnaiyan. “This study also highlights our international collaboration with Ke Ding, Ph.D., a medicinal chemist at the Shanghai Institute of Chemistry, in creating orally effective CDK12/13 degraders.”
The researchers aim to continue advancing the CDK12/13 degrader with the hope of launching clinical trials in the future.
