title: Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells.
abstract: 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 IC(50)/parental line IC(50)) 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 IC(50) 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.
authors.affiliation: Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaspar
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.forename: Simon
authors.initials: S
authors.lastname: Pacey
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.forename: Michael
authors.initials: M
authors.lastname: Walton
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Suzanne
authors.initials: S
authors.lastname: Eccles
authors.forename: Andrew
authors.initials: A
authors.lastname: Pearson
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D000077204:Temozolomide
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D012333:RNA, Messenger; C112765:tanespimycin; D003606:Dacarbazine; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D000077204:Temozolomide