Hsp90 as a therapeutic target in prostate cancer.
Prostate cancers are hormone-dependent malignancies that respond to drugs that reduce circulating testosterone levels or prevent binding of this ligand to the androgen receptor (AR). While effective, these approaches are not curative and, in almost all cases, progression to a castration-resistant state is eventually observed. The mechanisms underlying the development of hormone resistance are poorly defined but several molecular changes are commonly associated with this process. Since a common element of these resistance mechanisms is restoration of AR signaling, agents that target AR expression represent an attractive treatment option for prostate cancer patients with disease progression following castration. Prior to ligand binding, AR exists in a complex with heat shock protein 90 (Hsp90) and other co-chaperones. The AR-Hsp90 interaction maintains AR in a high-affinity ligand-binding conformation, which is necessary for efficient response to hormone. 17-Allyamino-17-demethoxygeldanamycin (17-AAG) is an inhibitor of the Hsp90 chaperone protein. Inhibition of Hsp90 function causes the proteasomal degradation of proteins that require this chaperone for maturation or stability. Hsp90 clients include several proteins of potential importance in mediating prostate cancer progression, including wild-type and mutated AR, HER2, and Akt. In murine models of prostate cancer, 17-AAG causes the degradation of these client proteins at nontoxic doses and inhibits the growth of hormone-naive and castration-resistant tumors. These data suggest that inhibitors of Hsp90 may represent a novel strategy for the treatment of patients with prostate cancer and clinical trials to test this hypothesis are currently ongoing.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
David B
DB
Solit
Howard I
HI
Scher
Neal
N
Rosen
D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists; D016227:Benzoquinones; D002369:Castration; D002455:Cell Division / Q000187:drug effects; D002986:Clinical Trials as Topic; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D047029:Lactams, Macrocyclic; D008024:Ligands; D008297:Male; D018832:Molecular Chaperones / Q000187:drug effects / Q000502:physiology; D009154:Mutation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000209:etiology / Q000517:prevention & control*; D011944:Receptors, Androgen / Q000502:physiology; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000502:physiology; D017211:Treatment Failure
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D018832:Molecular Chaperones; D011944:Receptors, Androgen; D017828:Rifabutin; D013739:Testosterone; C112765:tanespimycin