In:
Nature Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2018-09-06)
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.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-018-06067-7
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2018
detail.hit.zdb_id:
2553671-0