Human Gene Set: MCCOLLUM_GELDANAMYCIN_RESISTANCE_DN


Standard name MCCOLLUM_GELDANAMYCIN_RESISTANCE_DN
Systematic name M14386
Brief description Genes down-regulated in A549GARS cells (lung cancer) resistant to the geldanamycin and 17-AAG [PubChem=5476289;6440175].
Full description or abstract Despite studies that show the antitumor activity of Hsp90 inhibitors, such as geldanamycin (GA) and its derivative 17-allylamino-demethoxygeldanamycin (17-AAG), recent reports indicate that these inhibitors lack significant single-agent clinical activity. Resistance to Hsp90 inhibitors has been previously linked to expression of P-glycoprotein (P-gp) and the multidrug resistant (MDR) phenotype. However, the stress response induced by GA treatment can also cause resistance to Hsp90-targeted therapy. Therefore, we chose to further investigate the relative importance of P-gp and the stress response in 17-AAG resistance. Colony-forming assays revealed that high expression of P-gp could increase the 17-AAG IC(50) 6-fold in cells transfected with P-gp compared with parent cells. A549 cells selected for resistance to GA overexpressed P-gp, but verapamil did not reverse the resistance. These cells also overexpressed Hsp27, and Hsp70 was induced with 17-AAG treatment. When the GA and 17-AAG resistant cells were transfected with Hsp27 and/or Hsp70 small interfering RNA (siRNA), the 17-AAG IC(50) decreased 10-fold compared with control transfected cells. Transfection with siRNA directed against Hsp27, Hsp70, or Hsp27 and Hsp70 also increased sensitivity to EC78, a purine scaffold-based Hsp90 inhibitor that is not a P-gp substrate. We conclude that P-gp may contribute, in part, to resistance to 17-AAG, but induction of stress response proteins, such as Hsp27 and Hsp70, by Hsp90-targeted therapy plays a larger role. Taken together, our results indicate that targeting of Hsp27 and Hsp70 should be exploited to increase the clinical efficacy of Hsp90-directed therapy.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 18794130   Authors: McCollum AK,TenEyck CJ,Stensgard B,Morlan BW,Ballman KV,Jenkins RB,Toft DO,Erlichman C
Exact source Table 1S: Mean Difference (log2) < 0
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Source species Homo sapiens
Contributed by Jessica Robertson (MSigDB Team)
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identifier namespace		 AFFY_HG_U133
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