Introduction and the biology of EZH2 in ARPI-resistant prostate cancer

In this OncLive Insights series, Dr. Neeraj Agarwal (Huntsman Cancer Institute, University of Utah) and Dr. Alicia Morgans (Dana-Farber Cancer Institute) explore the role of EZH2 in prostate cancer treatment resistance.

Dr. Morgans opens by noting that while androgen receptor pathway inhibitors (ARPIs) have transformed advanced prostate cancer treatment, resistance eventually develops in nearly all patients. She highlights EZH2 as an enzyme overexpressed in most castration-resistant prostate cancers, with preclinical work suggesting it may both silence tumor suppressor genes and co-activate the androgen receptor, potentially contributing to ARPI resistance. She emphasizes that the biology is still evolving and that EZH2's effects may be more complex than a single mechanism.

Dr. Agarwal then explains EZH2's two key functions. In its standard (canonical) role, EZH2 acts as part of a protein complex called PRC2, where it chemically modifies the proteins that package DNA, effectively shutting down tumor suppressor genes and keeping cancer cells in a growth-promoting state. In its non-standard (non-canonical) role, EZH2 can directly interact with the androgen receptor — including resistant variants like AR-V7 — and help drive cancer-promoting gene activity even when ARPIs have lowered androgen levels. Dr. Agarwal explains that together, these functions promote cancer cell growth, block cell death, and can push tumor cells toward a neuroendocrine state that no longer depends on androgen signaling, all of which contribute to treatment resistance.

In the next episode, "EZH2 and lineage plasticity: complexity beyond simple reversal," the experts explore emerging preclinical data that challenge the simple reversal hypothesis of EZH2 inhibition.