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

¹ Signal Transduction and Molecular Pharmacology Team and ² Tumour Biology and Metastasis Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research; ³ Section of Paediatric Oncology, The Institute of Cancer Research and Royal Marsden Hospital NHS Foundation Trust, Sutton, Surrey, United Kingdom and ⁴ UPRES EA 3535, University Paris XI, IFR54, Pharmacology and New Treatments of Cancer, Institut de Cancérologie Gustave Roussy, Villejuif, France

Requests for reprints: Paul Workman, Cancer Research UK Center for Cancer Therapeutics, Haddow Laboratories, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44-208-722-4301; Fax: 44-208-722-4324; E-mail: Paul.Workman{at}icr.ac.uk.

Key Words: acquired 17-AAG resistance • NQO1 down-regulation • glioblastoma cell lines

Heat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), which is currently in phase II/phase III 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 (NQO1) expression/activity and 17-AAG IC₅₀ was observed in the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQO1 mRNA levels and NQO1 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQO1*2 polymorphism. Decreased NQO1 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 NQO1 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]

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				Correction: Article on In vitro Acquired Resistance to 17-AAG Cancer Res., April 15, 2009; 69(8): 3721 - 3721. [Full Text] [PDF]