New study uncovers how prostate cancer cells evade treatment

Cancer cells are remarkably good at adapting to stress. When treatments damage them, they often find new ways to survive, fueling drug resistance and disease progression.

Researchers at MUSC Hollings Cancer Center, led by Noel Warfel, Ph.D., uncovered one of those escape routes. Their study, published in Cancer Letters, revealed a previously unknown mechanism that helps prostate cancer cells to evade treatment and points to a potential strategy for overcoming that resistance.

The research focuses on PIM1, a protein that drives prostate cancer cells to grow, survive and resist treatment. Although scientists have spent years developing drugs to target PIM1, these therapies have shown limited success in patients with solid tumors.

We know that PIM1 is important for prostate cancer progression and resistance to therapy, but existing inhibitors haven't worked well in the clinic. This study gives us the first real insight into why that happens and suggests a new way to target the protein more effectively."

Noel Warfel, Ph.D., Associate Professor of Biochemistry and Molecular Biology at MUSC

When blocking a protein isn't enough

Most cancer drugs designed to target PIM1 work by inhibiting its kinase activity – the chemical signaling function that helps to drive tumor growth. But Warfel's team previously discovered that PIM1 has another side to its biology: Even when its signaling activity is blocked, the protein can continue promoting cancer cells' survival.

In the new study, researchers found that traditional PIM1 inhibitors create a biological double-edged sword. While the drugs successfully shut down PIM1 signaling activity, they also cause cancer cells to accumulate more PIM1 protein. As a result, the therapies leave behind a growing pool of PIM1 that can continue promoting cancer cells' survival through mechanisms unrelated to signaling activity.

"We're blocking one survival effect but at the same time increasing another side of the coin," Warfel said. "Just by being present in the cell, PIM1 can promote resistance."

That finding raised a critical question: If PIM1 is no longer signaling, how is it still helping cancer cells to survive?

A surprising partner

To answer that question, the researchers looked at proteins that interact with PIM1.

They identified a new binding partner: HMGB1, a multifunctional protein that normally resides in the cell nucleus, where it coordinates responses to DNA damage. However, when there is excess PIM1, it binds to HMGB1 and traps the protein in the cell's cytoplasm. There, HMGB1 switches on a cellular recycling process known as autophagy.

Through autophagy, cancer cells can remove damaged mitochondria. This is important because damaged mitochondria produce unstable molecules that can build up during treatment and destroy cancer cells. By clearing away damaged mitochondria, the PIM1-HMGB1 partnership effectively removes a source of cellular damage, helping tumors to survive therapies that might otherwise have been effective.

"When HMGB1 is in the cytoplasm, it activates autophagy and helps the cell get rid of damaged mitochondria," Warfel explained. "That reduces oxidative stress and allows cancer cells to survive challenges that would otherwise kill them."

Degrading the target

The findings also pointed to a possible solution.

Rather than simply inhibiting PIM1, Warfel's team previously developed a proteolysis-targeting chimera, or PROTAC, designed to destroy the protein entirely. Their experimental compound, known as PIMTAC, removes PIM proteins from cancer cells instead of merely blocking their activity.

In laboratory studies and mouse models, PIMTAC proved more effective than conventional PIM inhibitors. The treatment increased oxidative stress within cancer cells and led to greater cancer cell death. In effect, removing PIM1 prevented cancer cells from activating the newly discovered HMGB1-mediated survival pathway.

"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 findings add to growing evidence that many cancer-driving proteins have important functions beyond the activities scientists traditionally target with drugs. Simply shutting off a protein's signaling activity may not be enough if the protein continues influencing cancer cell behavior through other mechanisms. Because PIM proteins are active in multiple cancer types, including breast, lung and blood cancers, the implications could extend well beyond prostate cancer.

"The exciting part is that we're increasingly appreciating these kinase-independent functions of proteins," Warfel said. "A lot of drugs are designed simply to block activity, but in some cases, it may be more valuable to remove the protein completely."

The work remains in the preclinical stage. Before the approach can advance to clinical trials, researchers must improve how the large PROTAC molecule is delivered throughout the body and develop strategies to target it more precisely to tumors.

Nonetheless, Warfel believes the findings highlight the value of continuing to probe even well-studied cancer targets. For patients with advanced prostate cancer, treatment resistance remains one of the biggest challenges in care. By uncovering how cancer cells evade therapy, researchers hope to develop improved strategies to make existing treatments work longer and more effectively.

"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."