Acquired Resistance to 17-Allylamino-17-Demethoxygeldanamycin (17-AAG, Tanespimycin) in Glioblastoma Cells

被引：91

作者：

Gaspar, Nathatie ^{[3
,4
,5
]}

Sharp, Swee Y.

Pacey, Simon

Jones, Chris ^{[3
,4
]}

Walton, Mchael

Vassal, Gilles ^{[5
]}

Eccles, Suzanne ^{[2
]}

Pearson, Andrew ^{[3
,4
]}

Workman, Paul ^{[1
]}

机构：

[1] Inst Canc Res, Canc Res UK Ctr Canc Therapeut, Haddow Labs, Signal Transduct & Mol Pharmacol Team, Sutton SM2 5NG, Surrey, England

[2] Inst Canc Res, Canc Res UK Ctr Canc Therapeut, Tumour Biol & Metastasis Team, Sutton SM2 5NG, Surrey, England

[3] Inst Canc Res, Sect Paediat Oncol, Sutton SM2 5NG, Surrey, England

[4] Royal Marsden Hosp NHS Fdn Trust, Sutton, Surrey, England

[5] Univ Paris 11, UPRES EA 3535, IFR54, Inst Cancerol Gustave Roussy, Villejuif, France

来源：

CANCER RESEARCH | 2009年 / 69卷 / 05期

关键词：

HSP90 MOLECULAR CHAPERONE; SHOCK-PROTEIN; 90; PHASE-I; HEAT-SHOCK-PROTEIN-90; INHIBITORS; BREAST-CANCER; NAD(P)H-QUINONE OXIDOREDUCTASE-1; ANSAMYCIN ANTIBIOTICS; DT-DIAPHORASE; SOLID TUMORS; LINES;

D O I：

10.1158/0008-5472.CAN-08-3131

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Heat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), which is currently in phase II/phase M clinical trials, are promising new anticancer agents. Here, we explored acquired resistance to HSP90 inhibitors in glioblastoma (GB), a primary brain tumor with poor prognosis. GB cells were exposed continuously to increased 17-AAG concentrations. Four 17-AAG-resistant GB cell lines were generated. High-resistance levels with resistance indices (RI = resistant line IC50/parental line IC50) of 20 to 137 were obtained rapidly (2-8 weeks). After cessation of 17-AAG exposure, RI decreased and then stabilized. Cross-resistance was found with other ansamycin benzoquinones but not with the structurally unrelated HSP90 inhibitors, radicicol, the purine BIIB021, and the resorcinylic pyrazole/isoxazole amide compounds VER-49009, VER-50589, and NVP-AUY922. An inverse correlation between NAD(P)H/quinone oxidoreductase 1 (NQ01) expression/activity and 17-AAG IC50 was observed in the resistant lines. The NQ01 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQ01 mRNA levels and NQ01 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQ01*2 polymorphism. Decreased NQ01 expression was also observed in a melanoma line with acquired resistance to 17-AAG. No resistance was generated with VER-50589 and NVP-AUY922. In conclusion, low NQ01 activity is a likely mechanism of acquired resistance to 17-AAG in GB, melanoma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors. [Cancer Res 2009;69(5):1966-75]

引用

页码：1966 / 1975

页数：10

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