Researchers develop new method to prevent prostate cancer chemoresistance

The results of a recent study co-led by a University of Arizona Cancer Center researcher suggest that novel therapeutic molecules known as proteolysis targeting chimeras, or PROTACs, could help overcome resistance to a class of anti-cancer drugs that are used to treat a wide range of cancers. The results were published online in Cell Chemical Biology.

A kinase is a type of protein that cells use to perform specific functions. One specific kinase, the PIM kinase, has been connected to the survival and spread of cancer cells. To improve cancer treatment outcomes, scientists developed PIM kinase inhibitor drugs; however, some patients develop resistance to these drugs, causing their disease to progress despite treatment.

In response, researchers from the National Cancer Institute and the University of Arizona Health Sciences created and patented PIM-PROTACs. Instead of blocking PIM activity, the PROTACs eliminate the PIM1 protein entirely.

“We developed a drug that finds PIM in the cell, binds it and degrades the whole protein away,” said Noel Warfel, PhD, a UArizona Cancer Center member and associate professor of cellular and molecular medicine in the UArizona College of Medicine – Tucson. “We tested our PIM-PROTAC in prostate cancer models, and it works significantly better than currently available PIM inhibitors that have gone to trial.”

The PIM-PROTAC has promise for addressing oncological diseases other than prostate cancer, as PIM kinases also have been found to be switched on in breast, colon, endometrial, gastric and pancreatic cancers. 

Warfel worked with National Institutes of Health scientists Pedro Torres-Ayuso, PhD, John Brognard, MD, and Dawid Mehlich, MD, from the National Cancer Institute’s Laboratory of Cell and Developmental Signaling and Rolf Swenson, PhD, and Venkata Sabbasani, PhD, from the National Heart, Lung, and Blood Institute’s Chemistry and Synthesis Center.

Collectively, they hold the patent for the PIM PROTAC technology.

The research team created several different PROTACs targeting PIM kinases and tested them in a series of experiments with prostate cancer cells in petri dishes. They found that using PIM PROTACs to break down PIM kinases was more effective at limiting tumor growth than using PIM kinase inhibitors.

“By generating PROTACs to promote degradation of the target, we are able to overcome that mechanism of resistance,” Brognard said.

This was especially true when the researchers applied a chemotherapy drug in combination with PIM PROTACs. When the chemotherapy drug docetaxel was applied to the cell culture, about 12% of the cancer cells died. When docetaxel was combined with a PIM PROTAC, cell death increased to 40%.

The team will continue to test PIM PROTACs to pinpoint the catalytic-independent mechanisms used by PIM to promote cancer and improve the precision of targeting PIM kinases to develop more effective treatments.