PHILADELPHIA (November 29, 2023) — A new study co-authored by a researcher from the Lewis Katz School of Medicine at Temple University and Fox Chase Cancer Center helps explain why drugs targeting a type of enzyme called PIM kinases, which are known to play an important role in several cancers, have largely failed in clinical trials. The findings also indicate that another approach may be significantly more effective.
The study is a proof of concept that a different type of compound, called PIM proteolysis targeting chimeras, or PROTACs, overcomes the challenges of PIM kinase inhibitors to attack cancer cells successfully, said Pedro Torres-Ayuso, PhD, a co-author on the paper and an Assistant Professor in the Department of Cancer and Cellular Biology at the Katz School of Medicine.
“PIM kinases have been an attractive target for cancer therapy, but unfortunately, traditional approaches haven’t performed as well as expected. Our study provides evidence of a new way to intervene against this family of oncogenes,” added Torres-Ayuso, who is also an Assistant Professor in the Cancer Signaling and Microenvironment Research Program at Fox Chase.
PIM kinases promote tumor development in several ways, including helping cancer cells to proliferate, survive, and become resistant to chemotherapy, so it originally made sense to inhibit them with small molecules, Torres-Ayuso said. Why these drugs did not then work as expected in clinical trials was a mystery.
For the new study, the international team of researchers looked at cells from prostate cancer, a type of cancer where PIM activity has been widely studied. The scientists treated the cancer cells with multiple PIM inhibitors. While they confirmed that the inhibitor did succeed in blocking enzyme activity, they found that it increased levels of PIM proteins. Further study found that these proteins, even if inhibited, promoted tumor growth and resistance to docetaxel, a chemotherapy drug.
“That meant we needed a new way to target these PIM kinases,” Torres-Ayuso said.
The team turned the PIM inhibitors into PROTACs, a new class of drugs designed to degrade unwanted proteins in cells. They found that PROTACs not only inhibited the enzyme activity but also eliminated the PIM protein. They then compared PROTACs to PIM inhibitors by testing them on cancer cells.
“We found that degrading PIM kinases was more efficient in reducing cancer cell growth than their inhibition,” he said. “We not only reduced cell growth, we actually increased cancer cell death.”
The findings provide a stepping stone to developing new cancer therapies, said Torres-Ayuso. He noted that, in addition to prostate cancer, PIMs are known to play a role in multiple solid tumors, including breast and colon cancers, and some types of leukemias.
However, he cautioned that although PROTACs are moving into clinical trials and show promising results, more work is needed to develop PIM degrading drugs, which are larger than traditional inhibitor molecules and are not easily dissolved and absorbed, into a form that could be used in animal or human trials.
The study also highlights the need for scientists to consider all the functions enzymes might have when designing inhibitors or approaches to targeting them and not focus exclusively on the function they’re hoping to target.
The paper, “PIM1 Targeted Degradation Prevents the Emergence of Chemoresistance in Prostate Cancer,” was published in Cell Chemical Biology.