Researchers reveal mechanisms of how CDK12 alterations drive prostate cancer development

Researchers previously found loss of the CDK12 gene in about 7% of patients with metastatic prostate cancer, suggesting this alteration may be linked to a more-aggressive form of the disease. This was discovered from DNA and RNA sequencing from patient tumor samples. CDK12 also plays a role in some ovarian cancers.

To understand how CDK12 loss impacts cells on a molecular level, researchers created a mouse model to try to parallel the genetic alterations they were seeing in human prostate cancers.

"These back-to-back studies taken together are quite impressive. We created an animal model and then deciphered the mechanisms of how CDK12 loss actually drives prostate cancer," Chinnaiyan said.

Further, they found that knocking down CDK12/13 activated the AKT pathway, which plays a role in cancer development. Combining the CDK12/13 degrader with existing therapies targeting AKT resulted in a synergistic effect in destroying cancer cells. This suggests the potential to combine a CDK12/13 degrader with other approved therapies.

"It's well known that single therapies for cancer treatment have been challenging. Oftentimes patients develop resistance. If we can find the right combination, we could prevent resistance mechanisms from occurring. That's one of the benefits of finding an FDA-approved agent to combine with CDK12/13 degraders," Chinnaiyan said. "This study also highlights an international collaboration with Ke Ding, Ph.D., a medicinal chemist at the Shanghai Institute of Chemistry, in the development of orally bioavailable CDK12/13 degraders."

Researchers plan to further develop the CDK12/13 degrader with a goal of moving it to a clinical trial.

Source:

Michigan Medicine - University of Michigan

Journal references:

• Chang, Y., et al. (2024). Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2024.101752.
• Tien, J. C.-Y., et al. (2024). CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2024.101758.