P-glycoprotein-mediated resistance to Hsp90-directed therapy is eclipsed by the heat shock response

Andrea K. McCollum, Cynthia J. TenEyck, Bridget Stensgard, Bruce W. Morlan, Karla V. Ballman, Robert B. Jenkins, David O. Toft, Charles Erlichman

Research output: Contribution to journalArticle

55 Scopus citations

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 IC50 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 Hsp27and/or Hsp70 small interfering RNA (siRNA), the 17-AAG IC50 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.

Original languageEnglish (US)
Pages (from-to)7419-7427
Number of pages9
JournalCancer research
Volume68
Issue number18
DOIs
StatePublished - Sep 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    McCollum, A. K., TenEyck, C. J., Stensgard, B., Morlan, B. W., Ballman, K. V., Jenkins, R. B., Toft, D. O., & Erlichman, C. (2008). P-glycoprotein-mediated resistance to Hsp90-directed therapy is eclipsed by the heat shock response. Cancer research, 68(18), 7419-7427. https://doi.org/10.1158/0008-5472.CAN-07-5175