Molecular Characterization of Prostate Cancer Following Androgen Deprivation: The Devil in the Details

Abstract

Androgen-deprivation therapy (ADT) remains the mainstay of therapy for advanced prostate cancer (PCa). However, patients inevitably progress and become resistant to treatment targeting the androgen signaling axis. Castrationresistant PCa (CRPC) represents the final stage of the disease, with median survival of <2 yr. Despite the recent addition of new agents to the armamentarium against CRPC, it remains incurable and universally lethal. Many fundamental questions about ADT and CRPC remain largely unanswered: How does PCa adapt to ADT? What are the most common mechanisms of resistance? Can recurrence be predicted and averted? The molecular profiling of PCa following ADT holds the potential to unlock the biology of CRPC, possibly revealing biomarkers necessary to predict response to therapy and to identify early recurrence as well as potentially identifying novel therapeutic targets. In this issue of European Urology, Rajan et al. report on a pilot study of gene expression profiling of seven patients with advanced PCa, with paired samples before and after ADT [1]. Using RNA sequencing and bioinformatics approaches, the authors identify alterations in the Wnt/b-catenin signaling pathway following ADT. Furthermore, they show dysregulation of b-catenin in a subset of CRPCs in an independent cohort and a small amount of functional data in cell lines suggesting that inhibition of Wnt/b-catenin signaling may preferentially inhibit CRPC cell growth. The authors should be commended for an approach that attempts to directly interrogate the impact of ADT on PCa signaling pathways in patients and to elucidate the molecular events underlying the emergence of CRPC.