Cancer Cell Study Identifies Promising New Therapeutic Strategy for Aggressive Neuroendocrine Prostate Cancer
By Lynn McCain | August 5
Researchers at the University of Michigan have identified a previously unrecognized survival mechanism in neuroendocrine prostate cancer (NEPC), one of the most aggressive and difficult-to-treat forms of prostate cancer. The findings, which have been published in Cancer Cell, uncover a critical vulnerability in NEPC and suggest a novel dual-targeting strategy that could eventually lead to more effective treatment options for patients with advanced disease.
The study, led by Yuanyuan Qiao, PhD., and colleagues at the U-M Center for Translational Pathology, in collaboration with Arul Chinnaiyan, M.D., Ph.D., and the Rogel Cancer Center, builds on the team’s earlier work published in Nature Cancer in 2021 that first linked the lipid kinase PIKfyve and its inhibitor, ESK981, to prostate cancer treatment response.
A cancer that thrives under stress
Neuroendocrine prostate cancer often emerges after standard hormone-blocking therapies stop working, and it no longer depends on the androgen receptor pathway that most prostate cancer treatments target. It also grows in profoundly oxygen-starved (hypoxic) environments, a condition that would normally overwhelm a cell's internal protein-folding machinery and trigger its death.
The research team found that NEPC tumors instead adapt to this chronic cellular stress by relying heavily on a lipid-processing enzyme called PIKfyve. PIKfyve helps cells recycle damaged components and manage lipids through the lysosome, the cell's internal "recycling center." The team showed that PIKfyve is markedly elevated in NEPC tumor tissue compared with surrounding healthy tissue, and that shutting it down — either genetically or with drugs — is far more damaging to neuroendocrine tumors than to other forms of prostate cancer.
"NEPC tumors have essentially built their survival strategy around this stress-adaptation pathway," said Qiao. "That dependency is also their vulnerability."
Blocking one escape route reveals another — and how to close it
When the researchers inhibited PIKfyve using several different compounds, including ESK981 (a drug already in phase II clinical testing) and a purpose-built PIKfyve-degrading molecule, tumor cells didn't simply give up. Instead, they activated a backup survival program: a lipid-manufacturing pathway driven by a family of proteins called SREBPs, which ramp up cholesterol and fatty acid production to shore up cellular membranes under stress.
By tracing this compensatory pathway, the team found that pairing PIKfyve inhibitors with drugs that block fatty acid synthesis — such as the FASN inhibitor TVB-2640, itself already in clinical trials — cut off both of the tumor's stress-survival routes at once. In cell and animal models, this combination triggered a fatal overload of cellular stress signaling that conventional single-drug treatment could not achieve, leading to tumor cell death.
From the lab to potential patient benefit
The findings were validated across multiple patient-derived tumor models, including several established directly from patient specimens by the research team. Combined PIKfyve/FASN-targeted treatment slowed tumor growth and prolonged survival in these models without causing significant toxicity in safety studies. The PIKfyve-targeting strategy also strengthened the effect of cisplatin, a chemotherapy already used as a frontline treatment for NEPC, suggesting a path toward combining the new approach with existing standard-of-care regimens.
Because both classes of drugs used in the study — PIKfyve inhibitors and FASN inhibitors — are already being evaluated in clinical trials for other purposes, the researchers say the path toward testing this combination in patients could be relatively direct.
"This work reveals a fundamental metabolic weak point that's specific to this hard-to-treat cancer subtype," said Chinnaiyan. "By understanding how these tumors adapt to survive stress, we've identified a rational way to make that adaptation backfire on the cancer."
A Phase II clinical trial evaluating ESK981 is already underway at the Rogel Cancer Center, offering an opportunity to further explore the therapeutic potential of PIKfyve inhibition in patients with neuroendocrine prostate cancer.
The researchers believe their discovery opens the door to a new therapeutic strategy for one of prostate cancer's deadliest forms—a disease that currently has few effective treatment options and carries a poor prognosis once it emerges.
Note: This article is based on a manuscript accepted for publication in Cancer Cell and should not be released publicly until the journal publication and embargo requirements have been satisfied.
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Citations:
Zheng, Y., Cheng, C., Cao, Y., …Chinnaiyan, A.M., Qiao, Y. A Stress-Adaptive Lipid Kinas Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer. Cancer Cell 2026. https://doi.org/10.0.3.248/j.ccell.2026.07.003
Qiao, Y., Choi, J.E., Tien, J.C., …Chinnaiyan, A.M. Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockage in prostate cancer. Nature Cancer 2021:2:978-993. https://doi.org/10.1038/s43018-021-00237-1.
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