Dynamic Plasticity of Prostate Cancer Intermediate Cells During Androgen Receptor Targeted Therapy

Abstract

The prevalence of treatment induced small cell neuroendocrine prostate cancer (t-SCNC) is increasing due to the extended use of potent AR signaling inhibitors. Understanding the kinetics and potential for reversibility of t-SCNC progression has been hampered by the lack of model systems suitable for studying intermediate tumor cell states. Here, we define a transcriptional reporter model that provides dynamic measures of treatment induced changes in human prostate cancer cell subpopulations. With this system we have identified intermediate tumor cells, defined as double high in expression for prostate specific antigen (PSA) and neuron specific enolase (NSE) expression. This tumor cell subpopulation functions as a necessary and sufficient component for the cellular conversion to an NE transcriptional signature when under the selective pressure of androgen ablation or AR signaling inhibitors. Such transcriptional plasticity was found to be reversible in a hormone and genetic driver dependent manner. Our data provide novel and mechanistic in site for understanding the contribution of transition cell populations to the emergence of therapeutic resistance in advanced castration resistant prostate cancer (CRPC).