An international collaboration has identified a previously unrecognized vulnerability in prostate cancer cells that could improve treatment for one of the most common cancers in men.
The findings, published in the journal Proceedings of the National Academy of Sciences, were led by researchers from Flinders University in Australia and the South China University of Technology.
The study shows that two enzymes—PDIA1 and PDIA5—are essential for the growth, survival, and treatment resistance of prostate cancer cells.
These enzymes act as molecular protectors for the androgen receptor (AR), the protein that drives prostate cancer. When PDIA1 and PDIA5 are inhibited, the AR becomes unstable and is degraded, causing cancer cell death and tumor shrinkage in both in‑vitro cultures and animal models.
The researchers also discovered that combining PDIA1/PDIA5 inhibitors with enzalutamide, a standard prostate‑cancer drug, markedly enhanced the therapy’s effectiveness.
“We have uncovered a novel mechanism that prostate cancer cells use to safeguard the androgen receptor, a key driver of the disease,” said senior author Professor Luke Selth, Head of Prostate Cancer Research at Flinders Health and Medical Research Institute.
“Targeting these enzymes destabilises the AR and makes tumours more responsive to existing treatments such as enzalutamide.”
Lead author Professor Jianling Xie, who initiated the work at Flinders University, noted that the combination therapy performed well in patient‑derived tumour samples and in mouse models, indicating strong potential for clinical trials.
“This represents an exciting advance,” said Dr. Xie, now at the South China University of Technology. “PDIA1 and PDIA5 not only support cancer growth but are also promising targets for adjunctive therapies.”
Beyond protecting the AR, the enzymes help cancer cells cope with stress and sustain energy production. Inhibiting them damages mitochondria and induces oxidative stress, further weakening tumour cells.
“Simultaneously attacking the AR and the tumour’s energy supply makes PDIA1 and PDIA5 especially attractive drug targets,” added Dr. Xie. “It’s like cutting off both fuel and engine at once.”
Professor Selth cautioned that, while current PDIA1/PDIA5 inhibitors are encouraging, more work is needed to guarantee safety and efficacy for patients. Some existing compounds may affect healthy cells, so future studies will focus on developing safer inhibitors.
Prostate cancer is the second most common cancer in men worldwide. Although hormone therapy and AR‑targeting drugs have helped many patients, resistance remains a major hurdle. This new discovery could help overcome that challenge and improve outcomes for men with advanced disease.