How to cite: Crawford ED, and Petrylak DP. Targeting Epigenetic Resistance in Advanced Prostate Cancer: BET and DNMT Inhibition. Grand Rounds in Urology. July 2026. Accessed Oct 2026. https://grandroundsinurology.com/targeting-epigenetic-resistance-in-advanced-prostate-cancer-bet-and-dnmt-inhibition/
Summary
In this UroDummies presentation, E. David Crawford, MD, Editor-in-Chief of Grand Rounds in Urology and Professor of Urology at the University of California, San Diego, San Diego, California, speaks with Daniel P. Petrylak, MD, Director of Genitourinary Oncology, Professor of Medicine and Urology, Yale University Cancer Center, New Haven, Connecticut, about BET proteins, mechanisms associated with loss of androgen-related identity, and the rationale for combining BET and DNA methyltransferase (DNMT) inhibition.
Dr. Petrylak explains that prostate cancers with TP53 or RB1 loss can undergo changes under pressure from androgen receptor (AR)-targeted therapy. Cancer cells may lose their androgen-related identity and develop a lineage-plastic, AR-independent phenotype. These cells can metastasize, grow independently of androgen, and develop neuroendocrine features. They may become AR-negative and produce relatively little prostate-specific antigen (PSA) while remaining aggressive. BET proteins participate in transcription associated with this transition. Dr. Petrylak explains that BET inhibition can interfere with this pathway and potentially restore androgen sensitivity.
The discussion addresses previous clinical investigation of BET inhibition, including ZEN-3694. Dr. Petrylak notes that inhibiting one BET protein may allow others to become upregulated. He also discusses RIPTACs, which he describes as forming a bridge, binding to the androgen receptor, and causing cellular destruction by interfering with BET proteins. Combining BET inhibition with DNMT inhibition can reverse gene silencing while BET inhibition blocks oncogenic transcription.
Although neuroendocrine disease tends to emerge later, Dr. Petrylak raises the possibility of eventually targeting these pathways earlier to prevent the emergence of neuroendocrine cells in patients with TP53 mutations or RB1 loss. He identifies combined BET and DNMT inhibition as a potential future treatment approach for these patients.
ABOUT THE AUTHOR
Researcher-physician E. David Crawford, MD, Jack A. Vickers Director of Prostate Research and Professor of Urology at the University of California, San Diego, San Diego, California, has devoted his career in medicine to educating the public about men's health issues and finding effective techniques and procedures to address prostate cancer, the most common malignancy affecting men in the United States.
Daniel P. Petrylak, MD, is a Professor of Medicine, specializing in Medical Oncology and Urology, and Chief of Genitourinary Oncology at Yale University Cancer Center in New Haven, Connecticut. Dr. Petrylak is an internationally renowned medical oncologist and is considered a pioneer in the research and development of new drugs and treatments to fight cancers of the prostate, bladder, and kidney.
