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

Publication ,  Journal Article
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 ...
Published in: Nat Commun
September 6, 2018
Published version (DOI) Link to item

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.

Duke Scholars

Jiaoti Huang
Author Jiaoti Huang Pathology
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Published In

Nat Commun

DOI

10.1038/s41467-018-06067-7

EISSN

2041-1723

Publication Date

September 6, 2018

Volume

9

Issue

1

Start / End Page

3600

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Signal Transduction
  • Receptors, Androgen
  • Proto-Oncogene Proteins c-bcl-2
  • Prostatic Neoplasms, Castration-Resistant
  • Phenylthiohydantoin
  • Nitriles
  • Molecular Targeted Therapy
  • Mice, Knockout
  • Mice, Inbred NOD
 

Citation

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Li, Q., Deng, Q., Chao, H.-P., Liu, X., Lu, Y., Lin, K., … Tang, D. G. (2018). Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Commun, 9(1), 3600. https://doi.org/10.1038/s41467-018-06067-7
Li, Qiuhui, Qu Deng, Hsueh-Ping Chao, Xin Liu, Yue Lu, Kevin Lin, Bigang Liu, et al. “Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses.” Nat Commun 9, no. 1 (September 6, 2018): 3600. https://doi.org/10.1038/s41467-018-06067-7.
Li Q, Deng Q, Chao H-P, Liu X, Lu Y, Lin K, et al. Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Commun. 2018 Sep 6;9(1):3600.
Li, Qiuhui, et al. “Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses.” Nat Commun, vol. 9, no. 1, Sept. 2018, p. 3600. Pubmed, doi:10.1038/s41467-018-06067-7.
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. Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Commun. 2018 Sep 6;9(1):3600.

Published In

Nat Commun

DOI

10.1038/s41467-018-06067-7

EISSN

2041-1723

Publication Date

September 6, 2018

Volume

9

Issue

1

Start / End Page

3600

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Signal Transduction
  • Receptors, Androgen
  • Proto-Oncogene Proteins c-bcl-2
  • Prostatic Neoplasms, Castration-Resistant
  • Phenylthiohydantoin
  • Nitriles
  • Molecular Targeted Therapy
  • Mice, Knockout
  • Mice, Inbred NOD