A new clue to resistance in metastatic prostate cancer

In metastatic prostate cancer, androgen receptor (AR) signaling is both a major driver of disease and one of its most important therapeutic targets. For many patients, androgen receptor pathway inhibitors (ARPI), drugs that block this pathway, can keep the cancer under control for years.

But some prostate cancers progress toward an AR-independent state, associated with aggressive disease and limited benefit from further AR-directed therapy. The challenge is identifying those patients early enough to guide treatment decisions.

“These are our best drugs,” explained Dr. Steven Blinka, assistant professor in the Clinical Research Division at Fred Hutch. “We wanted to better understand who are those people that don’t respond well, and whether those patients might benefit from closer monitoring or more intensive treatment up front”.

A new study published in Clinical Cancer Research, led by Blinka and Dr. Andrew Hsieh, points to SPEN, a gene that appears to help keep prostate cancer dependent on androgen receptor signaling. Using an unbiased, genome-wide CRISPR screen, the researchers identified SPEN as one of the strongest hits associated with resistance to the androgen receptor pathway inhibitor enzalutamide.

“This work identifies a new context-specific tumor suppressor, SPEN, which when mutated drives resistance to androgen receptor pathway inhibitors,” Hsieh explained.

That context is key. When researchers deleted SPEN from prostate cancer cells growing without enzalutamide, the cells gained little advantage. But once androgen receptor signaling was blocked, the difference was striking. Cells lacking SPEN continued to proliferate while cells with intact SPEN were suppressed. After seven rounds of growth in enzalutamide, more than 95% of the surviving cells were SPEN-deficient. Tumors lacking SPEN also grew more readily in mice following androgen deprivation.

Together, these results led the researchers to describe SPEN as a conditional tumor suppressor. Its role in restraining cancer growth becomes apparent specifically when androgen receptor signaling is blocked.

The team then turned to the question of how losing SPEN might allow cancer cells to escape AR-directed therapy. Within days of enzalutamide treatment, SPEN-deficient cells activated programs that promote cell division and took on features of a more basal, stem-like cell state. In other words, the cells appeared to shift into a state that allowed them to keep proliferating even when androgen receptor activity was low.

The researchers also saw an increase in protein production. Their findings suggest that SPEN may influence this process indirectly through the integrated stress response, a cellular pathway that adjusts protein production when cells are under stress.

Exactly how SPEN connects these different responses remains an open question. “A major question is what is the molecular mechanism by which SPEN loss drives ARPI resistance,” Hsieh said. Changes in cell division signaling and stress-response pathways provide some clues, he added, but precisely how SPEN controls them is still unknown.

The researchers next asked whether the pattern they observed in the laboratory was also evident in patients.

They analyzed a nationwide dataset containing 6,828 patients with metastatic prostate cancer and found that SPEN mutations were more frequently observed following treatment with androgen receptor pathway inhibitors. The difference was also reflected in treatment outcomes. Among patients with metastatic hormone-sensitive prostate cancer, those with SPEN mutations needed another treatment much sooner than those without the mutation, suggesting that AR-targeted therapy was less effective at keeping their cancer under control.

SPEN mutations are relatively rare, appearing in only about 3–4% of metastatic prostate cancers. But the researchers found signs that the biology may extend beyond mutation alone. Low SPEN protein levels and a broader pattern of gene activity associated with SPEN loss were also linked to poorer outcomes on androgen receptor pathway inhibitors. Because SPEN works as part of a larger system that regulates gene activity, disruptions elsewhere in that system could potentially identify additional tumors with similar resistance.

More work is needed before SPEN can be used to guide treatment. Prospective studies will need to test whether SPEN loss, or changes in the broader pathway, can reliably identify patients who are likely to get less benefit from AR-targeted therapy. Tracking tumors before treatment and again after the cancer progresses could also help researchers understand when and how this resistance emerges.

Ultimately, the goal is to recognize these tumors earlier. If researchers can identify patients whose cancers are less likely to remain controlled by AR-targeted therapy, clinicians may be able to monitor them more closely or consider different treatment strategies sooner. Each new clue about how tumors resist treatment brings researchers closer to a more personalized approach that helps patients get the right treatment at the right time.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Steven Blinka, Peter Nelson, Michael Schweizer, and Andrew Hsieh contributed to this research.

The spotlighted research was funded by the National Institutes of Health, a Prostate Cancer Foundation Challenge Award, an American Cancer Society Discovery Boost Award, the Nancy & Dick Bernheimer, Matthews Family, Stinchcomb Family, and Thomas & Patricia Wright Memorial Funds, an ASCO YIA, the Larry and Virginia Gordon Endowed Chair, and a Foundation Medicine – Prostate Cancer Foundation Collaborative Research Award.

Blinka S, Arora S, Rudoy D, Gowda A, Yong P, Hwang Y, Nyquist MD, Graf R, Li G, Nelson PS, Schweizer MT, and Hsieh AC. 2026. SPEN inactivation drives resistance to androgen receptor pathway inhibitors in metastatic prostate cancer. Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-26-1405