New Target Identified to Overcome Resistance in Advanced Prostate Cancer
An international team of researchers has pinpointed a critical weakness in prostate cancer cells, offering hope for more effective treatments for this common cancer affecting men. The study,published in the Proceedings of the National Academy of Sciences (PNAS),was a collaborative effort lead by scientists from Flinders University in Australia and South China University of Technology.
The research focuses on two enzymes, PDIA1 and PDIA5, which protect a key protein driving prostate cancer growth – the androgen receptor (AR). Researchers found that blocking these enzymes destabilizes the AR, leading to cancer cell death and tumor shrinkage in laboratory and animal studies.
Importantly, combining drugs that inhibit PDIA1 and PDIA5 with the existing prostate cancer medication enzalutamide substantially boosted treatment effectiveness. “We’ve discovered a previously unknown mechanism that prostate cancer cells use to protect the androgen receptor,” explains Professor Luke Selth, Head of Prostate Cancer Research at Flinders University. “By targeting these enzymes, we can destabilize the AR and make tumors more vulnerable to existing therapies.”
Beyond protecting the AR, PDIA1 and PDIA5 also help cancer cells manage stress and maintain energy production. Blocking these enzymes damages the cell’s power generators (mitochondria), leading to oxidative stress and further weakening the cancer. Professor Jianling Xie, now at South China University of Technology, describes this as “cutting off both the fuel and the engine at the same time.”
While promising, current inhibitors of PDIA1 and PDIA5 require further refinement to minimize effects on healthy cells. Future research will focus on developing safer, more targeted compounds.
Despite advancements in treatments like hormone therapy and AR-targeting drugs, resistance remains a notable hurdle in treating advanced prostate cancer. This revelation offers a potential pathway to overcome that resistance and improve outcomes for men battling the disease.
This research was supported by Cancer Council SA, Cancer Council NSW, the Flinders Foundation, the Movember Foundation, the Prostate Cancer Foundation of Australia, The Hospital Research Foundation, Cancer Australia, Masonic Charities Trust, the Australian Research Council, and several international funding organizations.
