Combination of targeted therapies could help overcome treatment resistance in advanced prostate cancer

by Denise Heady, University of California, Los Angeles

edited by Sadie Harley, reviewed by Robert Egan

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UCLA researchers have identified a promising strategy to make a new class of targeted cancer therapies more effective against one of the deadliest forms of prostate cancer, potentially overcoming treatment resistance that has limited their success.

Metastatic castration-resistant prostate cancer, an aggressive form of the disease that no longer responds to hormone therapy, remains incurable despite advances in treatment. Antibody-drug conjugates (ADCs), precision medicines that deliver potent cancer-killing drugs directly to tumors, have transformed care for several cancers but have shown only modest and often short-lived benefits in prostate cancer.

But new research, led by investigators at the UCLA Health Jonsson Comprehensive Cancer Center and published in the Journal of Clinical Investigation, shows that combining ADCs with a drug that blocks a cancer cell survival protein called BCL-XL can make prostate cancer cells more susceptible to treatment.

In laboratory and animal models, the combination triggered greater cancer cell death and slowed tumor growth compared with either therapy alone, suggesting a potential new approach for developing the next generation of targeted therapies for advanced prostate cancer.

"Our findings show that these therapies offer tremendous engineering flexibility," said Dr. John Lee, associate professor-in-residence in the Division of Hematology/Oncology at the David Geffen School of Medicine at UCLA and co-senior author of the study.

"Rather than introducing a single new therapy, we've established a framework for building more effective antibody-drug conjugates by pairing complementary drug payloads and targeting multiple proteins on prostate cancer cells. That flexibility gives us an opportunity to better tailor these therapies to the biology of advanced prostate cancer."

Why prostate tumors resist ADCs

Antibody-drug conjugates have emerged as one of the most promising advances in precision oncology because they are designed to deliver potent chemotherapy directly to cancer cells while limiting damage to healthy tissue. Several ADCs have become standard treatments for breast, bladder and blood cancers, but they have not produced the same durable responses in metastatic prostate cancer.

Researchers have long hoped ADCs would change that. An ADC combines an antibody that recognizes a protein on cancer cells with a potent chemotherapy payload connected by a molecular linker that releases the drug once it reaches the tumor.

To address this issue, rather than designing a completely new therapy, Lee and his team looked for ways to improve existing ADCs.

"It's essentially a way of delivering chemotherapy with much greater precision," said Lee, who is an investigator in the UCLA Health Jonsson Comprehensive Cancer Center and at the UCLA Broad Stem Cell Research Center.

Two vulnerabilities at once

The researchers first analyzed tumor samples from patients with advanced prostate cancer and found that three proteins commonly targeted by ADCs—B7-H3, PSMA and STEAP1—are frequently found on the same cancer cells. That finding suggests multiple ADCs could potentially target the same tumor simultaneously, increasing the number of cancer cells reached while limiting exposure to healthy tissues.

The researchers then tested dozens of combinations of drugs commonly used as ADC payloads, looking for combinations that worked better together than expected. One combination consistently outperformed the others: DNA-damaging drugs paired with a compound that blocks BCL-XL, a protein cancer cells use to prevent programmed cell death.

Normally, cancer cells can survive significant DNA damage by activating protective pathways. Blocking BCL-XL removes one of those escape routes, making it much more difficult for damaged tumor cells to recover.

In prostate cancer cells grown in the laboratory, the combination triggered substantially more cell death than either treatment alone. Similar results were seen in mice with advanced prostate tumors, where the combination slowed tumor growth significantly more than either therapy by itself.

Clues for selecting patients

The researchers also found that tumors with an intact version of the TP53 tumor suppressor gene responded particularly well, suggesting genetic testing could eventually help identify patients most likely to benefit.

"We were surprised by how many unexpected payload combinations showed synergy," Lee said. "We're now engineering next-generation ADCs that incorporate these findings and testing additional combinations that could further improve treatment."

If the findings are confirmed in future clinical trials, the approach could offer a new strategy for improving antibody-drug conjugates against metastatic prostate cancer, where treatment resistance remains one of the greatest barriers to long-term disease control.

The study's first author is Galina Semenova at UCLA and the co-senior author is Dr. Peter Nelson of Fred Hutchinson Cancer Center.

Publication details

Galina Semenova et al, Genotoxic antibody-drug conjugates combined with BCL-XL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer, Journal of Clinical Investigation (2026). DOI: 10.1172/jci200438

Journal information: Journal of Clinical Investigation

Key medical concepts

Metastatic Castration-Resistant Prostate CarcinomaAntibody Drug Conjugates

Clinical categories

OncologyUrologyClinical pharmacologyMen's health Provided by University of California, Los Angeles Who's behind this story?

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