TY - JOUR
T1 - Acquired resistance to 17-Allylamino-17-Demethoxygeldanamycin (17-A AG, Tanespimycin) in glioblastoma cells
AU - Gaspar, Nathalie
AU - Sharp, Swee Y.
AU - Pacey, Simon
AU - Jones, Chris
AU - Walton, Michael
AU - Vassal, Gilles
AU - Eccles, Suzanne
AU - Pearson, Andrew
AU - Workman, Paul
PY - 2009/3/1
Y1 - 2009/3/1
N2 - Heat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17- demethoxygeldanamyein (17-AAG, tanespimy-cin), 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 (BI = resistant line KWparental 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 correla-tion between NAD(P)H/quinone oxidoreductase 1 (NQOl) expression/activity and 17-AAG IC50 was observed in the resistant lines. The NQOl inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQOl mBNA levels and NQOl DNA polymorphism analysis indicated different underlying mech-anisms: reduced expression and selection of the inactive NQ01*2 polymorphism. Decreased NQOl 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 NQOl activity is a likely mechanism of acquired resistance to 17-AAG in GB, melano-ma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors.
AB - Heat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17- demethoxygeldanamyein (17-AAG, tanespimy-cin), 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 (BI = resistant line KWparental 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 correla-tion between NAD(P)H/quinone oxidoreductase 1 (NQOl) expression/activity and 17-AAG IC50 was observed in the resistant lines. The NQOl inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQOl mBNA levels and NQOl DNA polymorphism analysis indicated different underlying mech-anisms: reduced expression and selection of the inactive NQ01*2 polymorphism. Decreased NQOl 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 NQOl activity is a likely mechanism of acquired resistance to 17-AAG in GB, melano-ma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=62449226171&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-3131
DO - 10.1158/0008-5472.CAN-08-3131
M3 - Article
C2 - 19244114
AN - SCOPUS:62449226171
SN - 0008-5472
VL - 69
SP - 1966
EP - 1975
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -