Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses.

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Li, Q; Deng, Q; Chao, H-P; Liu, X; Lu, Y; Lin, K; Liu, B; Tang, GW; Zhang, D; Tracz, A; Jeter, C; Rycaj, K; Calhoun-Davis, T; Huang, J; Rubin, MA; Beltran, H; Shen, J; Chatta, G; Puzanov, I; Mohler, JL; Wang, J; Zhao, R; Kirk, J; Chen, X; Tang, DG

Published Date

  • September 6, 2018

Published In

Volume / Issue

  • 9 / 1

Start / End Page

  • 3600 -

PubMed ID

  • 30190514

Pubmed Central ID

  • 30190514

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-06067-7

Language

  • eng

Conference Location

  • England