Hidden Weakness Makes Prostate Cancer Self-Destruct

A new study has uncovered a surprising vulnerability in prostate cancer’s survival system — and scientists believe it could change how we treat the disease.

The Enzymes That Shield Cancer

Prostate cancer cells rely on two enzymes, PDIA1 and PDIA5, to protect their most critical driver: the androgen receptor (AR). This receptor fuels tumour growth, helping cancer cells survive even during treatment.

Researchers found that PDIA1 and PDIA5 act like molecular bodyguards — keeping the AR stable and active. But when these enzymes are blocked, the AR collapses, the cancer cells lose their footing, and tumours shrink. It’s like pulling the plug on the cancer’s command centre.

A One-Two Punch Against Resistance

When scientists combined inhibitors of PDIA1 and PDIA5 with enzalutamide—a standard prostate cancer drug—the results were striking. The combination killed more cancer cells, worked faster, and stayed effective in drug-resistant models.

Professor Luke Selth, senior author of the study, explains:

“By targeting these enzymes, we can destabilize the AR and make tumors more vulnerable to existing therapies.”

Cutting Off the Fuel and the Engine

Beyond protecting the AR, PDIA1 and PDIA5 help cancer cells manage stress and produce energy. Blocking them damages mitochondria, creating oxidative stress that further weakens tumours.

“It’s like cutting off both the fuel and the engine,” says lead author Professor Jianling Xie. “We’re hitting cancer from two sides — its survival mechanism and its power supply.”

Toward Safer, Smarter Treatments

While early inhibitors show promise, researchers are now designing safer and more selective versions to avoid harming healthy cells.

Prostate cancer remains the second most common cancer in men worldwide, and drug resistance continues to limit long-term survival. This discovery — supported by organisations including Cancer Council SA, Movember Foundation, and Prostate Cancer Foundation of Australia — may pave the way for therapies that finally outsmart the disease.