Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Academic Article uri icon

Overview

abstract

  • Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR-/lo). Xenograft modeling demonstrates that AR+ CRPC is enzalutamide-sensitive but AR-/lo CRPC is resistant. Genome editing-derived AR+ and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR+/hi and AR-/lo CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR-/lo PCa cells/clones.

publication date

  • September 6, 2018

Research

keywords

  • Phenylthiohydantoin
  • Prostatic Neoplasms, Castration-Resistant
  • Receptors, Androgen

Identity

PubMed Central ID

  • PMC6127155

Scopus Document Identifier

  • 85052920806

Digital Object Identifier (DOI)

  • 10.1038/nprot.2016.006

PubMed ID

  • 30190514

Additional Document Info

volume

  • 9

issue

  • 1