The anti-proliferative effect of heat shock protein 90 inhibitor, 17-DMAG, on non-small-cell lung cancers being resistant to EGFR tyrosine kinase inhibitor

Naruyuki Kobayashi, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Hideaki Dote, Kensuke Kawasaki, Hiroki Otani, Takafumi Kubo, Masaru Jida, Tsuyoshi Ueno, Midori Ando, Atsuko Ogino, Katsuyuki Kiura, Shinichiro Miyoshi

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is frequently observed after initiation of TKIs therapy. Non-small-cell lung cancers (NSCLC) with activating EGFR mutations were reported to be sensitive to heat shock protein 90 (Hsp90) inhibitors regardless of the secondary TKI-resistant T790M mutation. We established EGFR-TKI resistant clones for PC-9 cell lines, harboring EGFR exon 19 deletions, with or without the secondary T790M mutation. We examined the anti-proliferative effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an orally active Hsp90 inhibitor, on the growth of NSCLC cell lines in vitro and in vivo. In MTS assay, the IC 50 values of 17-DMAG for 13 EGFR-mutant cell lines including eight EGFR-TKI resistant cell lines ranged from 0.04 to 0.16μM while those for seven EGFR-wild type cell lines ranged from 1.6 to 27.4μM. Western blot analysis revealed that phospho-EGFR, phospho-Akt, phospho-MAPK, cdk4, and cyclin D1 were more readily depleted by 17-DMAG treatment in EGFR-mutant cell lines than in EGFR-wild type cell lines. Cleaved PARP expression confirmed apoptosis in response to 17-DMAG treatment in EGFR-mutant cell lines but not in EGFR-wild type cell lines. In mice xenograft models, 17-DMAG significantly reduced the growth of EGFR-mutant lines irrespective of T790M mutation. These results suggested that 17-DMAG is a potential novel therapeutic agent for NSCLC patients with EGFR mutations with or without EGFR-TKI resistance.

Original languageEnglish
Pages (from-to)161-166
Number of pages6
JournalLung Cancer
Volume75
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • 17-DMAG
  • Acquired resistance
  • EGFR mutation
  • EGFR-TKI
  • Gefitinib
  • Hsp90
  • Hsp90 inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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