Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist.
The role of androgen receptor (AR) mutations in androgen-independent prostate cancer (PCa) was determined by examining AR transcripts and genes from a large series of bone marrow metastases. Mutations were found in 5 of 16 patients who received combined androgen blockade with the AR antagonist flutamide, and these mutant ARs were strongly stimulated by flutamide. In contrast, the single mutant AR found among 17 patients treated with androgen ablation monotherapy was not flutamide stimulated. Patients with flutamide-stimulated AR mutations responded to subsequent treatment with bicalutamide, an AR antagonist that blocks the mutant ARs. These findings demonstrate that AR mutations occur in response to strong selective pressure from flutamide treatment.
Taplin
M E
ME
University of Massachusetts Cancer Center, Worcester 01655, USA.
Bubley
G J
GJ
Ko
Y J
YJ
Small
E J
EJ
Upton
M
M
Rajeshkumar
B
B
Balk
S P
SP
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000813:Anilides / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D019046:Bone Marrow Neoplasms / Q000235:genetics* / Q000556:secondary; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D005485:Flutamide / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds
D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D003062:Codon; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D005485:Flutamide; C053541:bicalutamide