Researchers Uncover How a Key Oncogene Drives Prostate Cancer at Its Earliest Stage

Roughly half of all prostate cancers involve the oncogene ERG. Now a new study reveals a surprising discovery about how this cancer is formed at the earliest stages. 

Prostate cancer is a luminal disease, meaning it originates from or mimics the luminal cells of the prostate gland. Surprisingly, however, the study found that ERG drives cancer by reprogramming basal cells into luminal tumor cells, rather than transforming existing luminal cells directly.

This has important implications for treatment since ERG is currently considered an “undruggable” target. Current treatment strategies for prostate cancer focus on targeting the luminal cancer cells, which often yields incomplete responses and ultimately leads to acquired resistance. 

New Approaches to Treating Prostate Cancer

The findings could pave the way for new approaches that target ERG-driven prostate cancer at its source, potentially enabling earlier intervention and synergy with existing luminal-focused therapies.

“This is a new realization. We now know where luminal cancer cells arise in the first place, and we can now use that insight to guide better therapies for the most common subtype of prostate cancer,” said Weiran Feng, PhD, an Assistant Professor in the Nuclear Dynamics and Cancer Research Program and a member of the Cancer Epigenetics Institute at Fox Chase Cancer Center. Feng is the first and co-corresponding author on the study.

Feng, who joined Fox Chase in 2025, led the work as a postdoctoral researcher in the laboratory of senior author Charles Sawyers, MD, of Memorial Sloan Kettering Cancer Center.

“By targeting these luminal cancer cells at their source, we hope to not only improve early disease treatment but also to prevent the disease from changing into even more aggressive forms later on,” Feng said. 

Key Findings

• Focus on basal cells: Researchers were surprised by ERG’s “exquisite cellular context dependency” in transforming only basal, but not luminal cells.
• Mechanism: ERG initiates cancer by activating a “trans-differentiation” process in basal cells that causes not only rapid growth but also places them in a stem-like state. It is from this state that the luminal cancer cells are formed. 
• Potential drug targets: This process depends on a specific network of druggable proteins, including the transcription factor STAT3, and epigenetic enzymes KMT2A and DOT1L. 

Exploring Possible Treatments

Another surprising finding was that despite a strong dependency on KMT2A/MLL1, the ERG-driven prostate cancer model is independent of MENIN, a well-known KMT2A partner and the target of a Food and Drug Administration-approved inhibitor used in leukemia.

While this rules out direct translation of existing MENIN inhibitors for this context, it reveals previously under-appreciated MENIN-independent functions of KMT2A in ERG-driven prostate cancer.

“This closes one possible clinical avenue, but it also opens a new possibilities for epigenetic vulnerabilities in prostate cancer that can be exploited in the future,” he said.

Moving Prostate Cancer Research Forward

The findings will spawn follow-up research for Feng, whose lab focuses on studying the mechanisms and vulnerabilities of prostate cancer development and therapy resistance.

In addition to continuing to study the function of KMT2A to identify possible therapeutic targets, the team also plans to take a closer look at other genetic vulnerabilities identified by the study, some of which can be targeted with available pharmacological inhibitors. 

The study, “ERG-Driven Prostate Cancer Initiation is Cell-Context Dependent and Requires KMT2A and DOT1L,” was published in Nature Genetics.