Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy.
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 NH(2)-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.
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-5618, USA.
Mara P
MP
Steinkamp
Orla A
OA
O'Mahony
Michele
M
Brogley
Haniya
H
Rehman
Elizabeth W
EW
Lapensee
Saravana
S
Dhanasekaran
Matthias D
MD
Hofer
Rainer
R
Kuefer
Arul
A
Chinnaiyan
Mark A
MA
Rubin
Kenneth J
KJ
Pienta
Diane M
DM
Robins
D019943:Amino Acid Substitution; D000813:Anilides / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001344:Autopsy; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers; D005485:Flutamide / Q000627:therapeutic use; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D009154:Mutation; D009570:Nitriles / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D012334:RNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds / Q000627:therapeutic use
D000813:Anilides; D000970:Antineoplastic Agents; D017931:DNA Primers; D009570:Nitriles; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D005485:Flutamide; D003513:Cycloheximide; C053541:bicalutamide