Targeting Protective Enzymes Could Overcome Prostate Cancer Treatment Resistance

Hidden weakness makes prostate cancer self-destruct | ScienceDaily

International study identifies molecular mechanism that helps tumors resist therapy—and shows how to exploit it

Scientists have discovered a critical vulnerability in prostate cancer cells that could revolutionize treatment for the disease, particularly for patients whose tumors have become resistant to current therapies. The breakthrough centers on two enzymes that act as molecular bodyguards for cancer cells—and blocking them makes existing treatments work dramatically better.

The discovery comes at a crucial time. Prostate cancer incidence rates have reversed from a decline of 6.4% per year during 2007-2014 to an increase of 3.0% annually during 2014-2021, with the steepest increases in advanced-stage disease. An estimated 313,780 new cases will be diagnosed in 2025, with approximately 35,770 men expected to die from the disease.

The Resistance Problem

While modern androgen receptor inhibitors like enzalutamide have transformed prostate cancer care, most patients eventually develop resistance through various mechanisms including gene amplification, mutations, splice variants, and alternative signaling pathways. Understanding how cancer cells protect themselves from therapy has become one of the field's most pressing challenges.

How Cancer Cells Protect Themselves

An international team led by Professor Luke Selth from Flinders University in Australia and Professor Jianling Xie from South China University of Technology identified two enzymes—PDIA1 and PDIA5—that play a critical protective role. These protein disulfide isomerases are upregulated in prostate cancer and induced by androgen receptor signaling, creating a feedback loop that helps protect cancer cells.

"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," explains Professor Selth. "By targeting these enzymes, we can destabilize the AR and make tumors more vulnerable to existing therapies like enzalutamide."

The research, published in the Proceedings of the National Academy of Sciences, demonstrates that these enzymes function as molecular chaperones, helping cancer cells maintain the delicate balance of protein production and degradation necessary for survival.

A Triple Threat to Cancer Cells

When researchers blocked PDIA1 and PDIA5, they triggered a cascade of destructive effects in cancer cells. Disabling these enzymes causes redox stress, mitochondrial dysfunction, growth inhibition, and death of prostate cancer cells both in laboratory cultures and in animal models.

Most importantly, loss of PDIA1/PDIA5 activity leads to ubiquitination and degradation of the androgen receptor itself, with these chaperones regulating AR stability by mediating disulfide bond formation. Without a stable androgen receptor, prostate cancer cells cannot receive the growth signals they need to survive.

The effects extend beyond the androgen receptor. PDIA1 and PDIA5 help cancer cells manage stress and maintain energy production, with critical functions in both AR-driven and AR-independent cancer models. When blocked, the mitochondria—the cell's power generators—become damaged, creating oxidative stress that compounds the cancer cells' problems.

"This dual impact of hitting both the AR and the cancer's energy supply makes these enzymes especially attractive targets," Dr. Xie explains. "It's like cutting off both the fuel and the engine at the same time."

Combination Therapy Shows Promise

The most striking results came when researchers combined PDIA enzyme inhibitors with enzalutamide. The combination therapy worked well in patient-derived tumor samples and in mice, showing strong potential for future clinical trials. The strategy proved significantly more effective than either treatment alone.

This matters because combination approaches have shown increasing promise across prostate cancer research. Recent clinical trials demonstrated that enzalutamide combined with hormone therapy reduced the risk of death by more than 40% in men with high-risk biochemically recurrent prostate cancer. The TALAPRO-2 trial showed that combining a PARP inhibitor with enzalutamide significantly improved overall survival in metastatic castration-resistant prostate cancer patients.

Part of a Broader Strategy

The PDIA1/PDIA5 discovery fits into an expanding toolkit for combating treatment resistance. Novel strategies being explored include non-ligand-binding-domain AR inhibitors, potent AR degraders such as PROTACs (proteolysis-targeting chimeras), and bipolar androgen therapy.

PDI is overexpressed in various cancers including ovarian, prostate, lung, lymphoma, glioma, and melanoma, with inhibition causing accumulation of misfolded proteins that triggers cell death. A recent multicenter phase II trial demonstrated that PDI inhibitors can be safely administered to cancer patients, establishing proof-of-concept for this therapeutic approach.

The Road to Clinical Use

Current PDIA1 and PDIA5 inhibitors require further development to be made more specific, with teams in Australia and China working to develop new inhibitors and approaches that would target them specifically to prostate cancer cells. Some existing compounds affect healthy cells, which could cause unwanted side effects.

"First and foremost, we need to develop new inhibitor drugs that are more specific to PDIA1 and PDIA5," Professor Selth notes. "We also think that such drugs would benefit from approaches that would target them to prostate cancer cells, because these enzymes have important functions across a range of cells and tissues in the body."

The research team must also determine optimal dosing schedules, identify which patients are most likely to benefit, and establish whether the treatment can prevent or delay resistance to standard therapies. While promising, the therapy remains several years away from clinical availability.

Addressing Health Disparities

Black men face 1.7 times higher likelihood of being diagnosed with prostate cancer and 2.1 times higher likelihood of dying from the disease compared to White men, while American Indian and Alaska Native men have 12% higher mortality despite 13% lower incidence.

As new therapies emerge, ensuring equitable access will be crucial. The American Cancer Society recommends that all men discuss prostate cancer screening with their healthcare provider at age 50, but Black men and those with a family history should have that conversation at age 45.

Looking Forward

This discovery represents a fundamentally new approach—one that works with existing therapies rather than replacing them. By making cancer cells more vulnerable to current treatments, this strategy could extend the effectiveness of proven drugs and potentially delay or prevent resistance.

The diverse range of resistance mechanisms presents new challenges for long-term disease control, which may be addressable through early use of combination therapies guided by genomic landscape studies. The identification of PDIA1 and PDIA5 adds another weapon to this arsenal.

For now, patients should continue with prescribed treatment plans and discuss questions about emerging therapies with their oncologists. The research underscores the importance of continued investment in basic cancer biology, which provides the foundation for tomorrow's treatments.

The study received support from 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 partners.

Sources

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The Informed Prostate Cancer Support Group Newsletter provides updates on prostate cancer research and treatment developments for educational purposes. This information should not replace consultation with your healthcare provider. Always discuss treatment options and medical decisions with your oncologist.

 

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