EZH2 and lineage plasticity: complexity beyond simple reversal

Dr. Agarwal asks Dr. Morgans to discuss what is currently understood about EZH2's role in lineage plasticity, including emerging data that challenge the simple reversal hypothesis. Dr. Morgans notes that the science is still evolving and that recent preclinical data have complicated the long-held view that EZH2 inhibition can straightforwardly reverse lineage plasticity and resensitize castration-resistant prostate cancer to androgen receptor (AR) inhibition.

She explains that EZH2 inhibitors have shown promise in models that are transitioning from well-differentiated adenocarcinoma toward less differentiated neuroendocrine-type prostate cancer. However, in cancers already fully committed to the neuroendocrine state, EZH2 inhibition can fail to reverse the phenotype and may instead favor forward differentiation and increased tumor heterogeneity. Genetic or pharmacologic deletion of EZH2 in prostate cancer can rewire transcriptional networks, leading to diversification of neuroendocrine phenotypes and reshaping of the AR cistrome. This includes activation of the KLF family of transcription factors and a redirection of AR binding to KLF-associated sites, driving alternative lineage variants and contributing to cancer heterogeneity and complexity.

In the next episode, "Mechanistic rationale for combining EZH2 inhibition with enzalutamide," Dr. Morgans discusses why pairing EZH2 inhibitors with enzalutamide may overcome ARPI resistance, supported by preclinical and early clinical data.