Cancer cells have an excellent ability to adapt to stress. Once damaged by treatment, they often find new ways to survive, develop drug resistance, and progress the disease.
Researchers at MUSC Hollings Cancer Center, led by Dr. Noel Warfel, have discovered one such escape route. Their study, published in Cancer Letters, reveals a previously unknown mechanism that helps prostate cancer cells evade treatment and points to potential strategies to overcome their resistance.
The study focuses on PIM1, a protein that promotes prostate cancer cell proliferation, survival, and treatment resistance. Scientists have spent years developing drugs that target PIM1, but these treatments have shown limited efficacy in patients with solid tumors.
Although PIM1 is known to be important for prostate cancer progression and treatment resistance, existing inhibitors have not performed well in the clinic. This study provides the first real insight into why this happens and suggests new ways to target proteins more effectively. ”
Dr. Noel Warfel, MUSC Associate Professor of Biochemistry and Molecular Biology
When protein blocking alone is not enough
Most anticancer drugs designed to target PIM1 work by inhibiting its kinase activity, a chemical signaling function that drives tumor growth. But Warfel’s team had previously discovered that PIM1 has another side to its biology. The idea is that the protein can continue to promote cancer cell survival even when its signaling activity is blocked.
In a new study, researchers found that traditional PIM1 inhibitors create a biological double-edged sword. Although these drugs successfully block PIM1 signaling activity, they also cause cancer cells to accumulate more PIM1 protein. As a result, these treatments leave a growing pool of PIM1 that can continue to promote cancer cell survival through mechanisms unrelated to signaling activity.
“We’re blocking one survival effect, but we’re also increasing the other side of the coin,” Warfel said. “PIM1 promotes resistance just by being present inside cells.”
This finding raised a critical question: How does PIM1 help cancer cells survive even when it no longer signals?
unexpected partner
To answer that question, the researchers focused on proteins that interact with PIM1.
They identified a new binding partner, HMGB1. HMGB1 is 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 turns 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 accumulate during treatment and destroy cancer cells. The PIM1-HMGB1 collaboration effectively eliminates the cause of cellular damage by removing damaged mitochondria, helping tumors survive treatments that might otherwise be effective.
“When HMGB1 is in the cytoplasm, autophagy is activated and helps the cell remove damaged mitochondria,” Warfel explained. “This reduces oxidative stress and allows cancer cells to withstand challenges that would kill them.”
degrade the target
The findings also point to a possible solution.
Warfel’s team previously developed a proteolytic targeting chimera (PROTAC) designed to completely destroy the protein, rather than simply inhibiting PIM1. Their experimental compound, known as PIMTAC, removes PIM proteins from cancer cells rather than simply blocking their activity.
In laboratory studies and mouse models, PIMTAC has proven to be more effective than traditional PIM inhibitors. This treatment increased oxidative stress within cancer cells and increased cancer cell death. Indeed, removing PIM1 prevented cancer cells from activating the newly discovered HMGB1-mediated survival pathway.
“Our degraders remove both sides of the problem,” Warfel said. “It stops PIM signaling, but it also eliminates these kinase-independent survival effects, which is why we think it may be more effective.”
The discovery adds to the evidence that many cancer-driving proteins have important functions beyond the activities that scientists traditionally target with drugs. Simply blocking a protein’s signaling activity may not be sufficient if the protein continues to influence cancer cell behavior through other mechanisms. PIM proteins are active in multiple cancer types, including breast, lung, and blood cancers, so their impact could extend far beyond prostate cancer.
“What’s interesting is our increasing appreciation for kinase-independent protein functions,” Warfel said. “Many drugs are designed to simply inhibit activity, but in some cases it may be more valuable to remove the protein entirely.”
This research is still in the preclinical stage. Before this approach can advance to clinical trials, researchers need to improve how large PROTAC molecules are delivered throughout the body and develop strategies to more precisely target tumors.
Nevertheless, Warfel believes the findings highlight the value of continuing to investigate even well-studied cancer targets. Treatment resistance remains one of the biggest challenges in treatment for patients with advanced prostate cancer. By uncovering how cancer cells evade treatments, 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 in targets we’ve been studying for years, we’re discovering new biology that could make a big difference in future therapeutic efficacy.”
sauce:
Medical University of South Carolina
Reference magazines:
Liu, H. Others. (2026). Kinase-independent signaling by PIM1 promotes drug resistance by increasing mitophagy and reducing oxidative stress. cancer letter. DOI: 10.1016/j.canlet.2026.218611. https://www.sciencedirect.com/science/article/pii/S0304383526003745?via%3Dihub
