Breakthrough Discovery: New Enzyme Targets May Overcome Treatment Resistance in Prostate Cancer

Scientists Identify Enzymes Prolonging Prostate Cancer Survival

IPCSG Newsletter - October 2025

Bottom Line: Australian and Chinese researchers have identified two enzymes—PDIA1 and PDIA5—that act as "molecular bodyguards" protecting prostate cancer cells from treatment. Blocking these enzymes not only destabilizes the androgen receptor but also disrupts cancer cell energy production, offering a promising dual-action approach to enhance current therapies like enzalutamide.

The Discovery

An international collaboration led by Professor Luke Selth at Flinders University in Australia and Professor Jianling Xie at South China University of Technology has revealed that two protein disulfide isomerase (PDI) enzymes—PDIA1 and PDIA5—play a crucial role in helping prostate cancer cells grow, survive, and resist treatment. The findings, published in the Proceedings of the National Academy of Sciences (PNAS) in October 2025, represent a significant advance in understanding why many patients develop resistance to current therapies.

How These Enzymes Protect Cancer

These enzymes function as molecular bodyguards for the androgen receptor (AR), the protein that fuels most prostate cancers. The research team discovered that PDIA1 and PDIA5 have two critical functions:

  1. AR Stabilization: The enzymes regulate AR stability by mediating disulfide bond formation, specifically requiring cysteines at positions 669 and 844 in the AR's ligand-binding domain. When PDIA1 and PDIA5 are blocked, the AR becomes unstable and breaks down, leading to cancer cell death and tumor shrinkage in both lab-grown cells and animal models.

  2. Metabolic Support: Beyond protecting the AR, PDIA1 and PDIA5 help cancer cells manage stress and maintain energy production. Blocking them causes damage to the cells' mitochondria—the energy-generating structures—and leads to oxidative stress, which further weakens the cancer.

The research demonstrated that PDIA1 and PDIA5 are upregulated in prostate cancer and induced by the AR signaling axis itself, creating a feedback loop between these chaperones and the AR pathway.

Enhanced Treatment Effectiveness

The most clinically relevant finding involves combining PDI inhibitors with existing therapies. The team found that combining drugs that block PDIA1 and PDIA5 with enzalutamide, a widely used prostate cancer medication, significantly boosted treatment effectiveness. Professor Xie reported that the combination therapy worked well in patient-derived tumor samples and in mice, suggesting strong potential for future clinical trials.

The critical functions of these enzymes in redox homeostasis and cell survival were observed in both AR-driven and AR-independent models of prostate cancer, suggesting this approach may be effective even in cancers that have evolved beyond AR dependence.

Understanding Enzalutamide Resistance

This discovery is particularly important given the widespread problem of treatment resistance. Enzalutamide has proven benefits in multiple settings—from biochemically recurrent disease to metastatic castration-resistant prostate cancer. Recent data published in the New England Journal of Medicine showed that adding enzalutamide to standard hormone therapy can reduce the risk of death by more than 40% in men whose prostate cancer returns after surgery or radiation.

However, resistance remains a major challenge. Multiple mechanisms drive enzalutamide resistance, including AR gene amplification, AR splice variants, AR point mutations, alternative steroid pathways, and lineage plasticity. The newly discovered role of PDIA1 and PDIA5 in maintaining AR stability and function adds another piece to this complex puzzle and, importantly, provides a targetable mechanism to overcome resistance.

What's Next: The Path to Clinical Use

While these findings are promising, translation to clinical practice faces several hurdles. Professor Selth noted that while current drugs that block PDIA1 and PDIA5 show promise, more work is needed to make them safe and effective for use in patients. The drugs that can specifically target PDIA1 and PDIA5 need to be developed further so they don't affect healthy cells.

Professor Selth explained that the priority is to develop new PDI inhibitor drugs that are more specific to PDIA1 and PDIA5, with teams in both Australia and China currently working on this challenge. Since these enzymes have important functions across various cells and tissues in the body, approaches that target the drugs specifically to prostate cancer cells will likely be necessary.

Context: Why This Matters

Prostate cancer affects approximately 1.5 million men worldwide annually, making it the second most common cancer in men globally. While treatments have improved survival, the development of resistance to hormone therapies and AR-targeting drugs remains a major challenge limiting long-term disease control.

The dual mechanism of action—hitting both the AR and the cancer's energy supply simultaneously—makes these enzyme targets particularly attractive. As Professor Xie noted, it's like cutting off both the fuel and the engine at the same time, potentially making it more difficult for cancer cells to develop alternative survival pathways.

Looking Ahead

This research opens new avenues for combination therapy strategies. The work demonstrates that understanding the cellular machinery that supports oncogenic drivers like the AR can reveal novel therapeutic vulnerabilities. As PDI inhibitors advance through preclinical development, they may eventually join the arsenal of treatments available to overcome resistance in advanced prostate cancer.

For patients currently on enzalutamide or considering AR-targeted therapies, this research reinforces that combination approaches targeting multiple pathways simultaneously may offer the best hope for durable disease control. While these specific PDI inhibitors are not yet ready for clinical use, the findings contribute to the growing understanding of how to outsmart prostate cancer's ability to develop treatment resistance.

Sources and Citations

  1. Xie, J., Shen, K., Liang, W., Kuang, Z., Shrestha, R.K., Hanson, A.R., Townley, S.L., He, M., Yu, S., Zhou, P., Zhu, L., Gong, Z., Ao, X., Raof, S.R., Zhang, Q., Chen, K., Wei, J., Marri, S., Snel, M.F., Irani, S., Chen, L., Wang, L., McDougal, D.P., Bruning, J.B., Ou, M., Wang, S., Proud, C.G., Du, H., Butler, L.M., & Selth, L.A. (2025). Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival. Proceedings of the National Academy of Sciences, 122, e2509222122. https://doi.org/10.1073/pnas.2509222122

  2. Flinders University. (2025, October 15). New way to weaken cancer cells could supercharge prostate cancer treatment. Flinders University News. https://news.flinders.edu.au/blog/2025/10/15/new-way-to-weaken-cancer-cells-could-supercharge-prostate-cancer-treatment/

  3. Medical Xpress. (2025, October 13). Targeting enzymes to weaken cancer cells could supercharge prostate cancer treatment. https://medicalxpress.com/news/2025-10-enzymes-weaken-cancer-cells-supercharge.html

  4. GEN - Genetic Engineering & Biotechnology News. (2025, October). Prostate cancer therapy effectiveness boosted by combination with enzyme inhibition. https://www.genengnews.com/topics/cancer/prostate-cancer-therapy-effectiveness-boosted-by-combination-with-enzyme-inhibition/

  5. Ghoshal, A. (2025, October 19). Blocking newly discovered enzymes could boost prostate cancer treatment. New Atlas. https://newatlas.com/cancer/blocking-enzymes-prostate-cancer-treatment-boost

  6. Newsweek. (2025, October 15). Scientists discover prostate cancer's achilles heel. https://www.newsweek.com/scientists-discover-prostate-cancers-achilles-heel-10872048

  7. Shore, N.D., de Almeida Luz, M., De Giorgi, U., Gleave, M., Gotto, G.T., Pieczonka, C.M., Haas, G.P., Kim, C.S., Ramirez-Backhaus, M., Rannikko, A., Kalac, M., Sridharan, S., Rosales, M., Tang, Y., Tutrone, R.F., Venugopal, B., Villers, A., Woo, H.H., Wang, F., & Freedland, S.J. (2025). Improved survival with enzalutamide in biochemically recurrent prostate cancer. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2510310

  8. Wang, Y., Chen, J., Wu, Z., Ding, W., Gao, S., Gao, Y., & Xu, C. (2021). Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it. British Journal of Pharmacology, 178(2), 239-261. https://doi.org/10.1111/bph.15300

  9. Blatt, E.B. & Raj, G.V. (2022). Molecular mechanisms of enzalutamide resistance in prostate cancer. Frontiers in Endocrinology, 13, 788304. https://pmc.ncbi.nlm.nih.gov/articles/PMC8992629/

  10. Prekovic, S., van Royen, M.E., Voet, A.R., Geverts, B., Houtman, R., Melchers, D., Zhang, K.Y., Van den Broeck, T., Smeets, E., Spans, L., Houtsmuller, A.B., Joniau, S., Claessens, F., Pike, A.C., Gribbon, P., & Helsen, C. (2019). Molecular determinants for enzalutamide-induced transcription in prostate cancer. Nucleic Acids Research, 47(15), 8093-8106. https://pmc.ncbi.nlm.nih.gov/articles/PMC6821169/

This article summarizes recent peer-reviewed research and news reports. Individual treatment decisions should be made in consultation with your oncology team. The IPCSG provides this information for educational purposes and does not endorse specific treatments.

 

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