A team of Duke Pathology researchers has identified a key molecular driver of neuroendocrine prostate cancer (NEPC), paving the way for potential new therapeutic strategies for patients with limited treatment options. Their findings were published July 30, 2026, in Molecular Cancer Research.
The study, titled "DNMT3B Drives Neuroendocrine Lineage Plasticity and Aggressive Progression in Prostate Cancer," was led by first authors Jung Wook Park, PhD, Rollie Endowed Assistant Professor of Pathology; postdoctoral fellow Hyeryeon Jung, MS, PhD; PhD student Kelly Yunsol Jo; and graduate student Ziqin Wang. Johnston-West Endowed Pathology Chair Jiaoti Huang, MD, PhD, was among the study's co-authors.v
NEPC is a highly aggressive subtype of advanced prostate cancer associated with poor outcomes and resistance to standard therapies. Although drugs such as enzalutamide can effectively treat many prostate cancers by targeting androgen receptor signaling, tumors can evolve over time, adopting evasive characteristics that allow them to resist treatment. This process, known as lineage plasticity, can drive the development of NEPC and leave patients with few treatment options.
In the study, the research team identified the DNA methyltransferase DNMT3B as a central regulator of this transition. The team found that DNMT3B is elevated in treatment-resistant prostate cancer cells and expressed at even higher levels in neuroendocrine prostate cancer. Their findings show that DNMT3B helps coordinate the genetic programs that allow cancer cells to adopt neuroendocrine features and stem cell-like properties associated with aggressive disease progression.
"These findings identify DNMT3B as a critical driver of neuroendocrine prostate cancer development and progression," said Park. "By targeting this molecule, we may be able to interrupt the processes that allow prostate tumors to become resistant to treatment and evolve into a more aggressive form."
Using both laboratory and animal models, the researchers showed that genetic inhibition of DNMT3B suppressed tumor growth, impaired cancer cell proliferation, and triggered cancer cell death. The team further demonstrated that pharmacologic inhibition of DNMT3B using the experimental compound Nanaomycin A significantly reduced tumor growth and diminished molecular markers linked to neuroendocrine differentiation and stemness without apparent acute toxicity in vivo.
The study also uncovered a previously unrecognized reciprocal relationship between DNMT3B and REST, a transcriptional repressor involved in maintaining prostate cell identity. This discovery provides new insight into the molecular mechanisms that drive neuroendocrine transformation and treatment resistance in prostate cancer.
"Our ultimate goal is to translate discoveries like these into better treatment options for patients," said Park. "By pinpointing vulnerabilities in the pathways that fuel therapy resistance and disease progression, we can begin to develop more effective strategies for some of the most challenging prostate cancers."
The findings suggest that DNMT3B may represent a promising therapeutic target for patients with advanced, treatment-resistant prostate cancer. Additional studies will be needed to further evaluate DNMT3B-targeted approaches and explore their potential in future clinical applications.
Read the paper here. Learn more about the Park Lab here.