Gaspar, N., Sharp, S. Y., Pacey, S., Jones, C., Walton, M., Vassal, G., Eccles, S., Pearson, A., Workman, P. (2009) Acquired Resistance to 17-Allylamino-17-Demethoxygeldanamycin (17-AAG, Tanespimycin) in Glioblastoma Cells. CANCER RESEARCH, 69 (5). pp. 1966-1975. ISSN 0008-5472

Full text not available from this repository.

Abstract

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]

Item Type:	Article
Authors (ICR Faculty only):	Workman, Paul and Eccles, Sue and Pearson, Andrew and Jones, Chris
All Authors:	Gaspar, N., Sharp, S. Y., Pacey, S., Jones, C., Walton, M., Vassal, G., Eccles, S., Pearson, A., Workman, P.
Uncontrolled Keywords:	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
Research teams:	ICR divisions > Cancer Therapeutics > Tumour Biology & Metastasis ICR divisions > Cancer Therapeutics > Signal Transduction & Molecular Pharmacology ICR divisions > Cancer Therapeutics > Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) ICR divisions > Cancer Therapeutics > Paediatric Molecular Pathology ICR divisions > Molecular Pathology > Paediatric Molecular Pathology Closed research groups > Paediatric Drug Development & Clinical Trials
Depositing User:	Users 10 not found.
Date Deposited:	27 Mar 2009 10:03
Last Modified:	05 Aug 2015 10:33
URI:	http://publications.icr.ac.uk/id/eprint/7734

Actions (login required)

View Item