Cracking the code for prostate cancer

A large team of researchers led by Wouter Karthaus, head of the Endocrine Therapy Resistance and Molecular Genetics Lab at EPFL, and Eneda Toska at Johns Hopkins University have identified the enzyme KMT2D as a key epigenetic regulator in prostate cancer. Their study reveals that KMT2D plays a central role in shaping how prostate tumors grow, survive, and respond to therapy.

Resistant prostate cancer

Most prostate cancers rely on the androgen receptor to fuel their growth. These tumors are typically treated with hormone-based therapies that block androgen receptor signaling.

However, over time, many prostate cancers adapt and become resistant tumors that give rise to “castration-resistant prostate cancers” (CRPC). Some CPRCs continue to depend on androgen receptors, but others shift away from it altogether, becoming harder to treat.

A key enzyme

That’s where KMT2D comes in. The researchers discovered that this enzyme makes it easier for the androgen receptor to reach and switch on key genes involved in tumor growth. It does this by altering the structure of chromatin, which is the dense protein packaging of DNA in the cell.

As a result, that the androgen receptor and its helper proteins can access their target sites more effectively. This helps maintain the activity of androgen receptor-driven prostate cancers, which depend on this pathway to keep proliferating.

The study also found that KMT2D also plays a vital role in a particularly aggressive form of androgen receptor-independent CRPC known as the “stem cell-like” subtype. In these tumors, KMT2D sustains a hybrid cellular identity by regulating a different set of transcription factors, notably those in the AP-1 family like FOSL1, which are linked to stem-like behavior and therapy resistance.

The researchers found this by using genetically engineered prostate cancer cell lines, organoids derived from patients, single-cell sequencing, and animal models. Removing or silencing KMT2D disrupted the cancer cells’ ability to maintain their identities and made them more vulnerable to treatments.

In preclinical models, blocking KMT2D amplified the effectiveness of certain anti-cancer drugs (PI3K/AKT inhibitors and adenosine receptor inhibitors).

Implications

The findings suggest that KMT2D could be a valuable therapeutic target in prostate cancer. Disabling it could re-sensitize tumors to existing therapies or slow their progression into more aggressive forms. The work also reinforces the importance of tailoring treatments to specific tumor subtypes, and of using epigenetic profiling to guide therapy decisions.

Wouter Karthaus says: “With the ongoing surge in prostate cancer cases and the resulting increase of patients developing drug resistant disease, it is important to understand how prostate cancer becomes drug resistant and discover new treatment avenues. KMT2D represents such a new avenue.”

Other contributors

• Memorial Sloan Kettering Cancer Center
• KU Leuven
• University of Miami
• University of the Basque Country
• Basque Foundation for Science
• Sylvester Comprehensive Cancer Center
• AstraZeneca
• New York University Grossman School of Medicine