Researchers at MUSC Hollings Cancer Center, led by Noel Warfel, Ph.D., announced on June 16 that they have uncovered a previously unknown mechanism by which prostate cancer cells evade treatment. The study, published in Cancer Letters, reveals how the protein PIM1 helps these cells survive therapies and suggests a new strategy to overcome drug resistance.
The research highlights that while most drugs targeting PIM1 work by inhibiting its kinase activity—the function responsible for driving tumor growth—these inhibitors can inadvertently cause cancer cells to accumulate more PIM1 protein. According to Warfel, "We're blocking one survival effect but at the same time increasing another side of the coin. Just by being present in the cell, PIM1 can promote resistance."
To further understand this process, researchers examined proteins interacting with PIM1 and identified HMGB1 as a new binding partner. Normally located in the cell nucleus coordinating DNA damage responses, HMGB1 becomes trapped in the cytoplasm when excess PIM1 is present. In this location, HMGB1 activates autophagy—a recycling process that removes damaged mitochondria from cancer cells—thus reducing oxidative stress and allowing tumors to withstand treatments.
Warfel explained, "When HMGB1 is in the cytoplasm, it activates autophagy and helps the cell get rid of damaged mitochondria. That reduces oxidative stress and allows cancer cells to survive challenges that would otherwise kill them." To address this challenge, Warfel's team developed an experimental compound called PIMTAC—a proteolysis-targeting chimera (PROTAC)—which destroys PIM proteins entirely rather than just inhibiting their activity.
In laboratory studies and mouse models, PIMTAC increased oxidative stress within cancer cells and led to greater cell death compared to conventional inhibitors. "Our degrader gets rid of both sides of the problem," Warfel said. "It stops PIM signaling but it also eliminates these kinase-independent survival effects. That's why we think it has the potential to be more effective." The researchers note that because similar mechanisms may exist in other cancers where PIM proteins are active—including breast, lung, and blood cancers—the implications could extend beyond prostate cancer.
While still in preclinical stages with challenges remaining around delivery methods for PROTAC molecules and targeting precision, Warfel said these findings underscore ongoing progress: "We're always finding new ways to attack cancer," he said. "Even for targets we've been studying for years, we're uncovering new biology that could make a real difference in how well treatments work in the future."
