| First Author | Li Q | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 3600 |
| PubMed ID | 30190514 | Mgi Jnum | J:268707 |
| Mgi Id | MGI:6268004 | Doi | 10.1038/s41467-018-06067-7 |
| Citation | Li Q, et al. (2018) Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Commun 9(1):3600 |
| abstractText | 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. |
