A new study from researchers at the University of Michigan has identified a potential two-drug strategy for treating an aggressive form of prostate cancer that can emerge after standard hormone therapies stop working. The experimental treatment combines BET bromodomain inhibitors with DNA methyltransferase, or DNMT, inhibitors—two classes of epigenetic drugs that influence how cancer cells read and use their genetic instructions. In laboratory models and mice, the combination suppressed tumor growth more effectively than either drug alone and appeared to reverse many of the molecular changes associated with treatment-resistant disease. The findings, published in JCI Insight, offer a possible therapeutic direction for patients whose tumors have undergone a dramatic change in cellular identity.
Prostate cancer is among the most commonly diagnosed cancers in men, affecting approximately one in eight during a lifetime. Although many patients can be successfully treated, the disease becomes far more difficult to control after it spreads beyond the prostate. In the United States, prostate cancer remains the second-leading cause of cancer-related death in men. Most prostate tumors initially resemble normal prostate glands and retain a dependence on androgens, the male sex hormones that include testosterone. This biological dependence makes the androgen receptor an important treatment target. Drugs that block androgen production or prevent androgen receptor signaling are therefore central to the management of metastatic prostate cancer.
The initial response to androgen receptor inhibitors can be substantial, but resistance eventually develops in nearly all patients with advanced disease. Some tumors continue growing by finding alternative ways to activate androgen receptor signaling. Others take a more radical route: they reprogram their identity. Instead of maintaining the features of gland-forming prostate cells, these cancers may acquire characteristics associated with stem-like, neuroendocrine or other cellular states. This process, known as transdifferentiation, involves extensive changes in gene expression and cellular behavior. The resulting tumors are often less dependent on androgen signaling and may become far more difficult to detect and treat using conventional prostate cancer therapies.
The Michigan team focused on tumors in which two major tumor-suppressor genes, TP53 and RB1, have been lost. Previous research had connected the disappearance of these genes with prostate cancer transdifferentiation, but the molecular logic behind that association remained unclear. By comparing prostate cancer cell lines with different genetic backgrounds, the researchers found that the transition appeared to involve two coordinated processes. First, cells shut down genes associated with glandular prostate function. At the same time, they activated gene-regulatory programs linked to stem-cell-like identities and alternate developmental states. Rather than representing a single molecular switch, transdifferentiation appears to be a coordinated rewiring of the cancer cell’s regulatory system.
This distinction helped explain why an earlier therapeutic approach had only limited success. The researchers had previously shown that BET bromodomain inhibitors could interfere with the activation of alternate identity programs. BET proteins help control gene expression by recognizing acetylated histones, the proteins around which DNA is packaged. By disrupting these interactions, BET inhibitors can reduce the transcription of selected cancer-promoting programs. In the new study, however, the drugs slowed the growth of transdifferentiated prostate cancer cells without consistently killing them. The surviving cells retained enough flexibility to maintain the altered state and eventually continue progressing, suggesting that blocking the activation of new programs was not sufficient by itself.
The investigators therefore added DNMT inhibitors to the treatment strategy. DNA methyltransferases place chemical tags called methyl groups onto DNA, often reducing the activity of nearby genes. In cancer, abnormal DNA methylation can silence genes that would otherwise help maintain normal cellular identity or restrain tumor growth. DNMT inhibitors can remove or dilute some of these methylation marks as cells divide, allowing previously silenced genes to become active again. The drugs are already approved by the U.S. Food and Drug Administration for certain blood cancers, but their potential in transdifferentiated solid tumors remains under investigation. In this study, the researchers reasoned that DNMT inhibition might help restore glandular gene programs while BET inhibition suppressed the alternate programs supporting the transformed identity.
The combined treatment produced stronger effects than either drug alone in prostate cancer cell lines. According to the researchers, the two-drug regimen reduced cancer cell growth and reversed a substantial portion of the gene-expression changes associated with transdifferentiation. The results were also reproduced in mice carrying implanted tumors, where the combination slowed tumor growth more effectively than individual treatment. Notably, the researchers reported significant antitumor activity at doses lower than the recommended doses of the individual drugs, and the regimen was well tolerated by the animals. These findings suggest that the drugs may operate through complementary mechanisms: one limits the transcriptional machinery that sustains the abnormal cell state, while the other helps reactivate genes lost during the transition.
The study remains preclinical, and the results do not yet demonstrate that the combination is safe or effective in people with advanced prostate cancer. Epigenetic drugs can affect gene activity across many tissues, creating the possibility of side effects that may not be apparent in laboratory models or short-term animal experiments. The researchers are now working to determine which individual genes are responsible for the treatment response and whether molecular biomarkers can identify patients most likely to benefit. Such biomarkers could include patterns of TP53 and RB1 loss, DNA methylation signatures, or gene-expression profiles indicating that a tumor has begun adopting a stem-like or non-glandular identity.
An additional goal is to intervene before transdifferentiation becomes established. Once prostate cancer cells have fully shifted into an alternate state, they may be more adaptable and resistant to therapies designed for conventional glandular tumors. Detecting early signs of the transition could allow clinicians to use combination treatment before the cancer becomes deeply reprogrammed. The Michigan researchers also believe that the strategy may have relevance beyond prostate cancer. Similar forms of lineage plasticity and transdifferentiation are being studied in lung and pancreatic cancers, where tumor cells can escape treatment by changing their biological identity. If future studies confirm the mechanism, simultaneous targeting of epigenetic survival programs could become a broader strategy for cancers that evolve by rewriting their cellular blueprint.
Subject of Research: Animals
Article Title: Combined BET bromodomain and DNMT inhibition targets critical survival pathways in transdifferentiated prostate cancer
News Publication Date: 11-Aug-2026
Web References: https://insight.jci.org/articles/view/207543; https://doi.org/10.1172/jci.insight.207543
References: JCI Insight, “Combined BET bromodomain and DNMT inhibition targets critical survival pathways in transdifferentiated prostate cancer,” DOI: 10.1172/jci.insight.207543
Keywords: prostate cancer, metastatic prostate cancer, transdifferentiation, treatment resistance, androgen receptor inhibitors, BET bromodomain inhibitors, DNMT inhibitors, epigenetics, TP53, RB1, tumor suppressor genes, cancer cell identity, prostate cancer therapy, University of Michigan, JCI Insight
