Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance

Takeshi Shimamura, Danan Li, Hongbin Ji, Henry J. Haringsma, Elizabeth Liniker, Christa L. Borgman, April M. Lowell, Yuko Minami, Kate McNamara, Samanthi A. Perera, Sara Zaghlul, Roman K. Thomas, Heidi Greulich, Susumu Kobayashi, Lucian R. Chirieac, Robert F. Padera, Shigeto Kubo, Masaya Takahashi, Daniel G. Tenen, Matthew MeyersonKwok Kin Wong, Geoffrey I. Shapiro

Research output: Contribution to journalArticle

125 Scopus citations

Abstract

The epidermal growth factor receptor (EGFR) secondary kinase domain T790M non-small cell lung cancer (NSCLC) mutation enhances receptor catalytic activity and confers resistance to the reversible tyrosine kinase inhibitors gefitinib and erlotinib. Currently, irreversible inhibitors represent the primary approach in clinical use to circumvent resistance. We show that higher concentrations of the irreversible EGFR inhibitor CL-387,785 are required to inhibit EGFR phosphorylation in T790M-expressing cells compared with EGFR mutant NSCLC cells without T790M. Additionally, CL-387,785 does not fully suppress phosphorylation of other activated receptor tyrosine kinases (RTK) in T790M-expressing cells. These deficiencies result in residual Akt and mammalian target of rapamycin (mTOR) activities. Full suppression of EGFR-mediated signaling in T790M-expressing cells requires the combination of CL-387,785 and rapamycin. In contrast, Hsp90 inhibition overcomes these limitations in vitro and depletes cells of EGFR, other RTKs, and phospho-Akt and inhibits mTOR signaling whether or not T790M is present. EGFR-T790M -expressing cells rendered resistant to CL-387,785 by a kinase switch mechanism retain sensitivity to Hsp90 inhibition. Finally, Hsp90 inhibition causes regression in murine lung adenocarcinomas driven by mutant EGFR (L858R) with or without T790M. However, efficacy in the L858R-T790M model requires a more intense treatment schedule and responses were transient. Nonetheless, these findings suggest that Hsp90 inhibitors may be effective in T790M-expressing cells and offer an alternative therapeutic strategy for this subset of lung cancers.

Original languageEnglish (US)
Pages (from-to)5827-5838
Number of pages12
JournalCancer Research
Volume68
Issue number14
DOIs
Publication statusPublished - Jul 15 2008

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Shimamura, T., Li, D., Ji, H., Haringsma, H. J., Liniker, E., Borgman, C. L., ... Shapiro, G. I. (2008). Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance. Cancer Research, 68(14), 5827-5838. https://doi.org/10.1158/0008-5472.CAN-07-5428