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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1Signal Transduction and Molecular Pharmacology Team and 2Tumour Biology and Metastasis Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research; 3Section of Paediatric Oncology, The Institute of Cancer Research and Royal Marsden Hospital NHS Foundation Trust, Sutton, Surrey, United Kingdom and 4UPRES EA 3535, University Paris XI, IFR54, Pharmacology and New Treatments of Cancer, Institut de Cancérologie Gustave Roussy, Villejuif, France
* To whom correspondence should be addressed. E-mail: Paul.Workman{at}icr.ac.uk.
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Abstract |
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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]
Key Words: acquired 17-AAG resistance, NQO1 down-regulation, glioblastoma cell lines
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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]
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