EZH2 Suppression Diversifies Prostate Cancer Lineage Variant Evolution and Lacks Efficacy in Inhibiting Disease Progression

Abstract Advanced prostate cancer (PrCa) remains a leading cause of cancer-related death among men due to disease progression in nearly all patients on standard of care therapy targeting the androgen receptor. An important mechanism driving therapeutic resistance is lineage plasticity, which enables PrCa cells to reprogram into lineage variants no longer dependent on androgen receptor signaling. As inhibitors of the histone methyltransferase EZH2 are being evaluated clinically for the treatment of advanced PrCa, we investigated here how EZH2 affects PrCa lineage plasticity. Data from genetically engineered mice and human clinical samples demonstrated that genetic or pharmacological suppression of EZH2 altered chromatin to expand active transcription factor programs. These changes in gene expression during PrCa progression increased the diversity of PrCa lineage variants that arose. EZH2 suppression did not inhibit disease progression or therapeutic resistance in this context. These findings advance the current understanding of PrCa lineage plasticity and suggest EZH2 inhibitors may be less effective in treating PrCa prone to lineage plasticity.