Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses
NATURE COMMUNICATIONS(2018)
摘要
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.
更多查看译文
关键词
Cancer stem cells,Prostate cancer,Tumour heterogeneity,Urological cancer,Science,Humanities and Social Sciences,multidisciplinary
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要