According to a new study from researchers at the University of Pennsylvania’s Abramson Cancer Center, blocking the kinase CDK7 triggers a chain reaction that leads in the death of prostate cancer cells that have expanded and are resistant to current therapy.
CDK7 is the on/off switch that governs Med-1, a process that acts in tandem with the androgen receptor to induce prostate cancer growth, according to the researchers. In mice, researchers discovered that shutting off the switch causes cancer cells to die. The findings were reported today in Cancer Discovery.
The prostate gland is a type of gland. It’s normally the size and form of a walnut, but as you get older, it gets bigger. It surrounds the urethra, which is the tube that takes urine (wee) out of the body and sits beneath the bladder. The prostate’s major function is to aid in the production of semen, the fluid that contains sperm.
Prostate enlargement, prostatitis, and prostate cancer are the most frequent prostate issues. Androgen deprivation therapy is a common treatment for prostate cancer, but the majority of patients develop resistance to it over time, allowing the tumor to grow and spread.
Metastatic castration-resistant prostate cancer (CRPC) is the term for this type of malignancy. The US Food and Drug Administration has licensed two medications for these conditions, although patients report little or no long-term survival benefit from them.
One of the most common types of cancer is prostate cancer. Many prostate cancers are slow-growing and limited to the prostate gland, where they are unlikely to cause substantial harm. Some kinds of prostate cancer, on the other hand, grow slowly and require little or no treatment.
We know that AR does not work alone; that it needs Med-1 as its partner. Our study found a way to turn off Med-1, leaving AR without its co-pilot which means the cancer cannot grow and the cells eventually die.
Irfan A. Asangani
However, some types of prostate cancer grow rapidly and are more prone to spread. This is more prone to cause issues, and it requires treatment to prevent it from spreading. Prostate cancer that is discovered early, while it is still contained within the prostate gland, has the best chance of being treated successfully.
Because the androgen receptor (AR) is still the primary driver of cancer growth in CRPC, removing its activity is crucial. A new approach is required due to the disease’s resilience to medicines that target AR directly.
Despite the lack of further mutations or other genetic overexpression in these malignancies, the Penn team was able to uncover a new target thanks to “AR’s co-pilot,” as researchers named it.
“We know that AR does not work alone; that it needs Med-1 as its partner,” said the study’s senior author Irfan A. Asangani, PhD, an assistant professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania.
“Our study found a way to turn off Med-1, leaving AR without its co-pilot which means the cancer cannot grow and the cells eventually die.”
In both the lab and animal models, using an inhibitor to switch off CDK7 resulted in the death of CRPC cells. Because healthy cells have redundancies in place to deal with the loss of Med-1, researchers detected very few off-target consequences from this method, implying that only cancer cells die.
“Our theory is that these cancer cells are addicted to Med-1 and AR but other cells are not, so we’re essentially cutting them off from their addiction,” Asangani said.
CDK7 inhibitors are currently being explored in phase I clinical trials for a variety of cancers, including leukemia, lung cancer, glioblastoma, and breast cancer, according to Asangani, but this work demonstrates the logic for doing so in CRPC.
Reyaz ur Rasool, Ramakrishnan Natesan, and Qu Deng are co-first authors on the study. Other Penn authors include Shweta Aras, Priti Lal, Samuel Sander Effron, Erick Mitchell-Velasquez, Jessica M. Posimo, Lauren E. Schwartz, Daniel J. Lee, and Donita C. Brady.
