Scientists Uncover New Weak Spot in Prostate Cancer Cells, a Game-Changer for Treatment

Scientists Uncover New Weak Spot in Prostate Cancer Cells, a Game-Changer for Treatment

Scientists Discover Molecular "Achilles Heel" That Could Boost Prostate Cancer Treatment

International research identifies protective enzymes as new therapeutic targets to overcome drug resistance

Scientists have uncovered how prostate cancer cells shield themselves from treatment—and found a way to strip away that protection. The discovery could help doctors overcome one of the biggest challenges in treating advanced prostate cancer: resistance to hormone therapy.

An international team from Flinders University in Australia and South China University of Technology has identified two enzymes—PDIA1 and PDIA5—that act as molecular guardians for cancer cells, helping them survive, grow, and resist treatment. The findings were published in October 2025 in the Proceedings of the National Academy of Sciences.

How Cancer Cells Protect Themselves

The enzymes work by stabilizing the androgen receptor (AR), the protein that drives most prostate cancers. Think of the AR as the engine powering cancer growth—PDIA1 and PDIA5 keep that engine running smoothly by maintaining proper protein structure through a process called disulfide bond formation.

When researchers blocked these enzymes in laboratory studies, the results were striking: the androgen receptor became unstable and broke down, leading to cancer cell death and tumor shrinkage in both lab-grown cells and animal models.

"We've discovered a previously unknown mechanism that prostate cancer cells use to protect the androgen receptor, which is a key driver of the disease," explained Professor Luke Selth, Head of Prostate Cancer Research at Flinders University.

A Dual Attack Strategy

What makes this discovery particularly powerful is that these enzymes serve multiple roles in cancer survival. Beyond protecting the androgen receptor, PDIA1 and PDIA5 help cancer cells manage stress and maintain energy production. Blocking them damages the mitochondria—the cellular power plants—causing what scientists call oxidative stress.

"It's like cutting off both the fuel and the engine at the same time," said lead researcher Professor Jianling Xie.

Enhancing Current Treatments

The most immediately relevant finding for patients: combining PDIA1 and PDIA5 inhibitors with enzalutamide—a widely prescribed prostate cancer drug—significantly boosted treatment effectiveness. The combination worked well in patient-derived tumor samples and in animal studies.

This matters because while enzalutamide helps many men, most patients ultimately develop resistance to this treatment, usually within 8 to 18 months. Cancer cells develop resistance through multiple pathways, including AR gene mutations, splice variants that lack the drug-binding region, and activation of alternative growth pathways.

Why Treatment Resistance Happens

Understanding why treatments stop working is crucial for developing better therapies. Cancer cells exhibit accelerated protein production to fuel their rapid growth, creating a dependency on cellular machinery that maintains protein stability—which is exactly where PDIA1 and PDIA5 come in.

Resistance to hormone therapy remains a major challenge, with only about 30% of people with hormone-resistant disease surviving more than 5 years. This new approach could help extend survival by preventing or delaying resistance.

The Road Ahead

While the laboratory results are promising, Professor Selth cautioned that more work is needed to develop safer, more specific inhibitors. Current compounds that block PDIA1 and PDIA5 may affect healthy cells, so future studies will focus on creating drugs that specifically target cancer cells.

"First and foremost, we need to develop new PDI inhibitor drugs that are more specific to PDIA1 and PDIA5—our teams in Australia and China are working hard on this right now", Selth said. The researchers are also exploring ways to deliver these drugs specifically to prostate cancer cells, since these enzymes have important functions throughout the body.

What This Means for Patients

Recent studies have shown that many doctors are not yet following updated treatment guidelines that recommend combination therapies for metastatic hormone-sensitive prostate cancer, even though clinical trials show these approaches help people live longer. Patients may need to advocate for themselves to ensure they're receiving optimal care.

If clinical trials of PDIA1/PDIA5 inhibitors prove successful, this approach could eventually join other emerging strategies for combating treatment-resistant prostate cancer, including:

• Combination therapies with enzalutamide that have reduced death risk by more than 40% in recent trials
• PARP inhibitors for patients with BRCA1, BRCA2, and related DNA repair mutations
• Radioligand therapies like Pluvicto for PSMA-positive metastatic castration-resistant prostate cancer
• Bispecific antibodies that help immune cells attack cancer

The discovery represents an important step in understanding how prostate cancer cells survive under treatment pressure. By targeting these protective enzymes, researchers may be able to make existing therapies work better and longer, potentially improving outcomes for men with advanced disease.

As always, discuss any questions about emerging treatments with your oncology team, and consider asking whether you might be eligible for clinical trials testing new approaches.

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Sources

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