17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts.
OBJECTIVE
Ansamycin antibiotics, including 17allylamino-17-demethoxygeldanamycin (17-AAG), inhibit Hsp90 function and cause the selective degradation of signaling proteins that require this chaperone for folding. Because mutations in the androgen receptor (AR) and activation of HER2 and Akt may account, in part, for prostate cancer progression after castration or treatment with antiandrogens, we sought to determine whether an inhibitor of Hsp90 function could degrade these Hsp90 client proteins and inhibit the growth of prostate cancer xenografts with an acceptable therapeutic index.


METHODS
The effect of 17-AAG on the expression of Hsp90 regulated signaling proteins in prostate cancer cells and xenografts was determined. The pharmacodynamics of target protein degradation was associated with the toxicology and antitumor activity of the drug.


RESULTS
17-AAG caused the degradation of HER2, Akt, and both mutant and wild-type AR and the retinoblastoma-dependent G1 growth arrest of prostate cancer cells. At nontoxic doses, 17-AAG caused a dose-dependent decline in AR, HER2, and Akt expression in prostate cancer xenografts. This decline was rapid, with a 97% loss of HER2 and an 80% loss of AR expression at 4 h. 17-AAG treatment at doses sufficient to induce AR, HER2, and Akt degradation resulted in the dose-dependent inhibition of androgen-dependent and -independent prostate cancer xenograft growth without toxicity.


CONCLUSIONS
These data demonstrate that, at a tolerable dose, inhibition of Hsp90 function by 17-AAG results in a marked reduction in HER2, AR, and Akt expression and inhibition of prostate tumor growth in mice. These results suggest that this drug may represent a new strategy for the treatment of prostate cancer.
Solit
David B
DB
Program in Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Zheng
Fuzhong F
FF
Drobnjak
Maria
M
Münster
Pamela N
PN
Higgins
Brian
B
Verbel
David
D
Heller
Glenn
G
Tong
William
W
Cordon-Cardo
Carlos
C
Agus
David B
DB
Scher
Howard I
HI
Rosen
Neal
N
D000728:Androgens / Q000502:physiology; D000818:Animals; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D016193:G1 Phase / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017430:Prostate-Specific Antigen / Q000097:blood / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000187:drug effects / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000502:physiology; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017430:Prostate-Specific Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011944:Receptors, Androgen; D016160:Retinoblastoma Protein; D017828:Rifabutin; C112765:tanespimycin