Dynamic plasticity of prostate cancer intermediate cells during androgen receptor-targeted therapy

Treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) is associated with an epithelial line-age switch from an androgen receptor (AR)-positive to neuroendocrine (NE)-marker-positive status. Under-standing the potential for reversibility of this aggressive disease state has been hampered by the paucity of models suitable for studying rate-limiting, transitional, or intermediate tumor cell subpopulations. We define a dual reporter model that measures acute transcriptional changes in response to castration or AR targeting agents. We identify steady-state transcriptional heterogeneity in AR and NE biomarkers, including interme-diate subpopulations that are coordinately high for prostate-specific antigen (PSA) and neuron-specific eno-clase (NSE) promoter activity. In the presence of castration or AR inhibitors, intermediate cells were neces-sary and sufficient for therapy-induced conversion of human PC cells to an NSE-high transcriptional status. Using hormone add-back studies, treatment-induced PSA-NSE transcriptional plasticity was reversible in PTEN-deficient PC cells but not in the presence of secondary genetic driver genes, including MYCN.