A major international study has uncovered a new vulnerability in prostate cancer cells that could transform treatment. The study reveals a hidden weakness in prostate cancer cells — and a way to exploit it.
Prostate cancer is the second most common cancer in men worldwide. Although treatments like hormone therapy and AR-targeting drugs have helped many patients, resistance to these therapies is a major challenge.
Researchers from Australia and China have found two enzymes that help cancer resist treatment. The experiments show that by blocking these could supercharge existing drugs and open the door to new therapies. This could be a major step forward in overcoming drug resistance in advanced prostate cancer.
The research reveals that two enzymes — PDIA1 and PDIA5 — play a crucial role in helping prostate cancer cells grow, survive, and resist treatment. These enzymes act as molecular bodyguards for the androgen receptor (AR), a protein that fuels prostate cancer. When PDIA1 and PDIA5 are blocked, the AR becomes unstable and breaks down, leading to cancer cell death and tumour shrinkage in both lab-grown cells and animal models.
The scientists also found that combining drugs that block PDIA1 and PDIA5 with enzalutamide, a widely used prostate cancer medication, significantly boosted the treatment’s effectiveness.
“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,” says senior author, Professor Luke Selth in a research note.
Selth adds: “By targeting these enzymes, we can destabilise the AR and make tumours more vulnerable to existing therapies like enzalutamide.”
The findings show that PDIA1 and PDIA5 are not just helpers of cancer growth but they’re also promising targets for new treatments that could work alongside existing drugs.
The role of these enzymes goes beyond protecting the AR. The study found that PDIA1 and PDIA5 also help cancer cells manage stress and maintain energy production.
Specifically, blocking them causes damage to the cells’ mitochondria — the parts of the cell that generate energy — and leads to oxidative stress, which further weakens the cancer. This dual impact of hits both the AR and the cancer’s energy supply makes these enzymes especially attractive targets.
While current drugs that block PDIA1 and PDIA5 show promise, more work is needed to make them safe and effective for use in patients. Some of the existing compounds may affect healthy cells, so future studies will focus on developing safer inhibitors.
The study appears in the journal Proceedings of the National Academy of Sciences. The research paper is titled “Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival.”
