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Molecular determinants of resistance to antiandrogen therapy

Nature Medicine volume 10, pages 33–39 (2004)Cite this article

Abstract

Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.

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Figure 1: Androgen receptor expression in hormone-sensitive (HS) and hormone-refractory (HR) xenografts.
Figure 2: Androgen receptor overexpression causes hormone refractory progression.
Figure 3: Androgen receptor expression is necessary for hormone sensitive–to–hormone refractory progression.
Figure 4: Androgen receptor–mediated progression occurs by a ligand-dependent, genotropic mechanism.
Figure 5: Increased androgen receptor expression converts antagonists to agonists.
Figure 6: Increased androgen receptor expression converts antagonists to weak agonists.

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Acknowledgements

We thank C. Gregory from University of North Carolina–Chapel Hill for providing CWR22 RNA and protein; I. Mellinghoff for reagents; and K. Ellwood-Yen, M. Carey, T. Graber, J. Nicoll, J. Xu, A. Kwon and members of the Sawyers lab for helpful discussions. This work was supported by grants from the National Cancer Institute, Department of Defense and CapCURE. C.L.S. is an Investigator of the Howard Hughes Medical Institute and a Doris Duke Distinguished Clinical Scientist.

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Author notes

  1. Charlie D Chen and Derek S Welsbie: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of California at Los Angeles, Los Angeles, 90095, California, USA

    Charlie D Chen, Chris Tran, Randy Chen & Charles L Sawyers

  2. Departments of Molecular Pharmacology and Urology, University of California at Los Angeles, Los Angeles, 90095, California, USA

    Charles L Sawyers

  3. Molecular Biology Institute, University of California at Los Angeles, Los Angeles, 90095, California, USA

    Derek S Welsbie & Charles L Sawyers

  4. Howard Hughes Medical Institute, University of California at Los Angeles, Los Angeles, 90095, California, USA

    Chris Tran, Sung Hee Baek, Michael G Rosenfeld & Charles L Sawyers

  5. David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, 90095, California, USA

    Charlie D Chen, Derek S Welsbie & Charles L Sawyers

  6. University of California at San Diego School of Medicine, San Diego, 92093, California, USA

    Sung Hee Baek & Michael G Rosenfeld

  7. Department of Urology, University of Washington, Seattle, 98195, Washington, USA

    Robert Vessella

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Correspondence to Charles L Sawyers.

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Chen, C., Welsbie, D., Tran, C. et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 10, 33–39 (2004). https://doi.org/10.1038/nm972

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