This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-3605v1 69/10/4434    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Steinkamp, M. P. Articles by Robins, D. M. Search for Related Content PubMed PubMed Citation Articles by Steinkamp, M. P. Articles by Robins, D. M.

Treatment-Dependent Androgen Receptor Mutations in Prostate Cancer Exploit Multiple Mechanisms to Evade Therapy

Departments of ¹ Human Genetics, ² Pathology, and ³ Medicine and Urology, University of Michigan Medical School, Ann Arbor, Michigan; ⁴ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁵ Department of Urology, University of Ulm, Ulm, Germany; and ⁶ Department of Pathology, Weill Cornell Medical College, New York, New York

Requests for reprints: Diane M. Robins, Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-5618. Phone: 734-764-4563; Fax: 734-763-3784; E-mail: drobins{at}umich.edu.

Key Words: androgen receptor • prostate cancer • antiandrogen resistance • flutamide • bicalutamide

Mutations in the androgen receptor (AR) that enable activation by antiandrogens occur in hormone-refractory prostate cancer, suggesting that mutant ARs are selected by treatment. To validate this hypothesis, we compared AR variants in metastases obtained by rapid autopsy of patients treated with flutamide or bicalutamide, or by excision of lymph node metastases from hormone-naïve patients. AR mutations occurred at low levels in all specimens, reflecting genetic heterogeneity of prostate cancer. Base changes recurring in multiple samples or multiple times per sample were considered putative selected mutations. Of 26 recurring missense mutations, most in the NH₂-terminal domain (NTD) occurred in multiple tumors, whereas those in the ligand binding domain (LBD) were case specific. Hormone-naïve tumors had few recurring mutations and none in the LBD. Several AR variants were assessed for mechanisms that might underlie treatment resistance. Selection was evident for the promiscuous receptor AR-V716M, which dominated three metastases from one flutamide-treated patient. For the inactive cytoplasmically restricted splice variant AR23, coexpression with AR enhanced ligand response, supporting a decoy function. A novel NTD mutation, W435L, in a motif involved in intramolecular interaction influenced promoter-selective, cell-dependent transactivation. AR-E255K, mutated in a domain that interacts with an E3 ubiquitin ligase, led to increased protein stability and nuclear localization in the absence of ligand. Thus, treatment with antiandrogens selects for gain-of-function AR mutations with altered stability, promoter preference, or ligand specificity. These processes reveal multiple targets for effective therapies regardless of AR mutation. [Cancer Res 2009;69(10):4434–42]