Researchers find drug combo that slows treatment-resistant prostate cancer

Overview

Updated Sep 8

Some prostate cancer tumors survive treatment by changing what they are—losing glandular identity and adopting stem-cell-like traits, a process called transdifferentiation. A University of Michigan team showed in JCI Insight that combining two drug classes reverses many of those changes and sharply slows tumor growth in mice.

Treatment-resistant prostate cancer has few options once tumors stop responding to hormone therapy. The combination approach targets the identity switch itself, and the team plans to develop clinical trials to test it in patients.

Why it matters

Treatment-resistant prostate cancer has few options today. This drug combo targets the resistance mechanism itself, potentially adding years for patients who run out of choices.

Questions about this story

Free account needed to ask — your question is kept and asked for you right after sign-up. Answers are public.

No questions yet — be the first to ask.

Key Indicators

Drug classes combined

BET bromodomain inhibitors plus DNA methyltransferase (DNMT) inhibitors, tested together for the first time.

Genes tied to resistance

Loss of TP53 and RB1 drives the cell identity switch that lets tumors evade treatment.

Preclinical

Research stage

Results come from prostate cancer cell lines and mouse models; human trials have not yet started.

Voices

Curated perspectives — historical figures and your fellow readers.

Ever wondered what historical figures would say about today's headlines?

People Involved

Joshi Alumkal

Professor of Internal Medicine-Hematology/Oncology, University of Michigan; member of Rogel Cancer Center

Leading the research team behind the JCI Insight study

Will Storck

Research Lab Specialist, Alumkal laboratory

Key researcher on the study; performed gene expression analysis

Organizations Involved

Michigan Medicine

Academic Medical Center

Institution hosting the research team

The academic medical center at the University of Michigan, home to the Rogel Cancer Center and the Alumkal laboratory.

JCI Insight

Peer-Reviewed Medical Journal

Publication venue for the study

A peer-reviewed journal published by the American Society for Clinical Investigation, focused on translational and clinical research.

Timeline

June 2026 September 2026

2 events Latest: September 8th, 2026 · 2 months ago

September 2026
JCI Insight publishes two-drug combination study
Latest Publication

University of Michigan researchers show BET bromodomain and DNMT inhibitors together reverse transdifferentiation and slow tumor growth in mice.
September 8th, 2026
June 2026
PIM1-targeting drug shows promise in resistant prostate cancer
Research finding

A separate research team reports that degrading PIM1 with a PROTAC molecule increases oxidative stress in prostate cancer cells and improves cell death.
June 16th, 2026

Scenarios

Michigan team launches phase 1 trial of BET/DNMT combination

Possible Resolves by End of 2027

Discussed by: Alumkal and colleagues at Michigan Medicine, who stated in the study they hope to develop clinical trials

The combination moves from mouse models to patients with transdifferentiated prostate cancer. A phase 1 trial would test safety, dosing, and preliminary efficacy. The team's stated goal is to determine whether the approach benefits patients whose tumors have already changed identity.

Researchers identify genes driving the antitumor effect

Likely Resolves by Q2 2028

Discussed by: The research team; Storck said they want to determine which genes are primarily responsible for the observed tumor suppression

Follow-up experiments pinpoint the specific genes whose reactivation produces the antitumor response. This would enable biomarker-driven patient selection and could sharpen the therapy's targeting.

Combination approach extends to lung and pancreatic cancers

Possible Resolves by End of 2028

Discussed by: The research team, who noted the strategy could have implications beyond prostate cancer, including lung and pancreatic tumors

Researchers test the BET/DNMT combination in other cancers that undergo transdifferentiation. Lung and pancreatic cancers share similar lineage-plasticity mechanisms, so positive results would broaden the therapy's reach.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

Documented since the 1990s

Neuroendocrine transformation of prostate cancer (clinical phenomenon)

Under prolonged androgen deprivation, a subset of prostate adenocarcinomas transform into small cell neuroendocrine carcinomas—an aggressive form with a fundamentally different cellular identity. This is the clinical manifestation of lineage plasticity, the same phenomenon the new study targets.

Then

Patients who transform typically progress rapidly on hormone therapy and have poor survival.

Now

Established the concept that prostate cancer cells can change identity under treatment pressure, transforming how researchers think about resistance.

Why this matters now

The transdifferentiation in the new study is the same biological phenomenon, now addressed mechanistically with drugs rather than just observed.

2015-2017

CDK4/6 inhibitors for hormone-resistant breast cancer (2015-2017)

Palbociclib, ribociclib, and abemaciclib were approved after trials showed that adding a CDK4/6 inhibitor to hormone therapy extended progression-free survival in advanced breast cancer patients whose tumors had developed resistance.

Then

Combination therapy became the standard of care for metastatic HR-positive, HER2-negative breast cancer.

Now

Demonstrated that blocking the specific pathways resistance mechanisms rely on can meaningfully extend survival.

Why this matters now

Shows the path from preclinical discovery to clinical standard of care when a second drug targets the resistance mechanism directly.

2015

Osimertinib for EGFR T790M-resistant lung cancer (2015)

After first-generation EGFR inhibitors stopped working because of a new resistance mutation (T790M), osimertinib was developed to target that specific resistance mechanism. Trials showed dramatic response rates in patients who had progressed on earlier drugs.

Then

Osimertinib became standard second-line therapy, then moved to first-line treatment.

Now

Established that understanding a specific resistance mechanism allows the development of drugs that hit it directly.

Why this matters now

Like the Michigan approach, it turns knowledge of the resistance mechanism into a targeted treatment strategy, rather than just managing symptoms of progression.