When researchers at the University of Michigan Rogel Cancer Center first identified a new subtype of aggressive prostate cancer, they knew they had to understand how this genetic change drove the cancer and how to target it with therapy.
In two new publications, both published at Cell Reports Medicinedo both, describing the mechanisms of how changes in the CDK12 gene drive prostate cancer development and reporting a promising knockdown agent that targets CDK12 and a related tumor-killing gene.
The researchers previously found loss of the CDK12 gene in about 7% of patients with metastatic prostate cancer, suggesting that this change may be linked to a more aggressive form of the disease. This was discovered by sequencing DNA and RNA from patient tumor samples. CDK12 also plays a role in some ovarian cancers.
To understand how loss of CDK12 affects cells at a molecular level, the researchers created a mouse model to try to parallel the genetic alterations seen in human prostate cancers.
What was quite surprising was when we created loss of CDK12 in mouse prostate, it caused precursor lesions to form in the mouse prostate. Then, when we added loss of the p53 oncogene, the mice developed bona fide invasive prostate cancer. It will be an addition to the field to have a genetically engineered mouse model that parallels what we see in human prostate cancer.”
Arul M. Chinnaiyan, MD, Ph.D., senior author, director of the Michigan Center for Translational Pathology and SP Hicks Professor of Pathology at Michigan Medicine
With the mouse model, the researchers then discovered the mechanism of how loss of CDK12 causes DNA damage. The loss of this gene activates other known cancer driver genes, causing them to be overexpressed at a high level, while also causing DNA to copy too quickly. The collision of these two processes leads to DNA damage.
“These back-to-back studies together are quite impressive. We created an animal model and then deciphered the mechanisms of how loss of CDK12 actually drives prostate cancer,” Chinnaiyan said.
The team also found that a partner gene, CDK13, is important for therapeutic targeting of the lesion. They developed a potential therapy designed to degrade CDK12 and CDK13. Tests in cell lines and mice showed that the knockdown specifically binds to CDK12 and CDK13 and stops the growth of cancer cells over normal cells. The degradative can be absorbed orally and does not need to be administered intravenously. This is notable as most protein degraders are too large to be absorbed orally, which has limited their potential in drug development.
In addition, they found that knockdown of CDK12/13 activated the AKT pathway, which plays a role in cancer development. Combining the CDK12/13 knockdown with existing therapies targeting AKT resulted in a synergistic effect in killing cancer cells. This suggests the possibility of combining a CDK12/13 knockdown with other approved therapies.
“It’s known that single therapies to treat cancer have been challenging. Often patients develop resistance. If we find the right combination, we could prevent resistance mechanisms from emerging. That’s one of the benefits of finding an FDA-approved agent for combination 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 available CDK12/13 degraders. .”
The researchers plan to further develop the CDK12/13 knockdown with the goal of moving it into a clinical trial.
Source:
Journal References:
- Chang, Y., et al. (2024). Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality by inhibition of the AKT pathway. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2024.101752.
- Tien, JC-Y., et al. (2024). Loss of CDK12 leads to prostate cancer progression, transcription-replication conflicts, and synthetic lethality with the CDK13 paralog. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2024.101758.
