Clonal Evolution and Epithelial Plasticity in the Emergence of AR-Independent Prostate Carcinoma

In spite of an initial clinical response to androgen deprivation therapy (ADT), the majority of prostate cancer patients eventually develop castration-resistant prostate cancer (CRPC). Recent studies have highlighted the role of epithelial plasticity, including transdifferentiation and epithelial-to-mesenchymal transition (EMT), in the development of AR pathway-negative CRPC, a form of the disease that has increased in incidence after the introduction of potent AR inhibitors. In this review, we will discuss the switches between different cell fates that occur in response to AR blockade or acquisition of specific oncogenic mutations, such as those in TP53 and RB1, during the evolution to CRPC. We highlight the urgent need to dissect the mechanistic underpinnings of these transitions and identify novel vulnerabilities that can be targeted therapeutically.