期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-06067-7
关键词
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资金
- US National Institutes of Health (NIH) [R01-CA155693]
- Department of Defense [W81XWH-13-1-0352, W81XWH-14-1-0575, W81XWH-16-1-0575]
- CPRIT [RP120380]
- Chinese Ministry of Science and Technology (MOST) [2016YFA0101203, P01-CA77739]
- RPCCC
- NCI [P30CA016056]
- DOD [PC141581]
- National Natural Science Foundation of China [81602592]
- CRPIT Core Facility Support Award [RP120348]
Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening similar to 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.
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