The heterogeneity of prostate cancers lacking AR activity will require diverse treatment approaches

Abstract

The use of androgen deprivation therapy and second line anti-androgens in prostate cancer has led to the emergence of tumors employing multiple androgen receptor (AR)-dependent and AR-independent mechanisms to resist AR targeted therapies in castration-resistant prostate cancer (CRPC). While the AR signaling axis remains the cornerstone for therapeutic development in CRPC, a clearer understanding of the heterogeneous biology of CRPC tumors is needed for inno-vative treatment strategies. In this review, we discuss the characteristics of CRPC tumors that lack AR activity and the temporal and spatial considerations for the conversion of an AR-dependent to an AR-independent tumor type. We describe the more prevalent treatment-emergent phenotypes aris-ing in the CRPC disease continuum, including amphicrine, AR-low, double-negative, neuroendo-crine and small cell phenotypes. We discuss the association between the loss of AR activity and tumor plasticity with a focus on the roles of transcription factors like SOX2, DNA methylation, alterna-tive splicing, and the activity of epigenetic modifiers like EZH2, BRD4, LSD1, and the nBAF complex in conversion to a neuroendocrine or small cell phenotype in CRPC. We hypothesize that only a subset of CRPC tumors have the propensity for tumor plasticity and conversion to the neuroendo-crine phenotype and outline how we might target these plastic and emergent phenotypes in CRPC. In conclusion, we assess the current and future avenues for treatment and determine that the heter-ogeneity of CRPCs lacking AR activity will require diverse treatment approaches.

Proteomic and Transcriptomic Profiling Reveals Mitochondrial Oxidative Phosphorylation as Therapeutic Vulnerability in Androgen Receptor Pathway Active Prostate Tumors

“…The majority of the samples correlated positively ( p > 0.7) within each subtype of PC and showed moderate-to-high correlation across different subtypes between AR-positive and AR-null ( p > 0.4). In general, the correlation among AR-positive tumor samples was lower than in AR-null tumors, indicating the heterogeneous nature of the AR-positive population, similarly as observed in a recent study using AR-positive biopsies [ 18 ]. These data show similar inter-tumor and intra-tumor heterogeneity in the LuCaP PDX samples to the heterogeneity observed in the clinical samples.…”

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

“…Simultaneously removal of the AR protein and androgens will result in robust cell death, leading to a possible curative result or long-term disease-free survival. In addition, early reduction of the AR protein in the androgen-responsive phase of prostate cancer will reduce the likelihood of transcriptional reprogramming ( 88 , 93 , 147 ). Also, tissue-specific delivery of the AR protein degradation agents will restrict potential side effects.…”

Characterization of Proteins Regulated by Androgen and Protein Kinase a Signaling in VCaP Prostate Cancer Cells

“…In one of these approaches, Dr. Morrissey and Dr. Nelson and colleagues characterized metastatic CRPC and cell lines into five phenotypes depending on the AR or NE genes [87,88]. According to their phenotypes, VCaP cell lines are considered as amphicrine (AMPC) expressing both AR and NE genes, which are used to define the molecular characteristics of samples used for expression analysis in cell lines and clinical samples (Figure 6a,b and Figure S3).…”