HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs

Sho Watanabe, Yasushi Goto, Hiroyuki Yasuda, Takashi Kohno, Noriko Motoi, Yuichiro Ohe, Hiroyoshi Nishikawa, Susumu S. Kobayashi, Kazuyoshi Kuwano, Yosuke Togashi

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third-generation EGFR-TKIs overcome this resistance by selectively inhibiting EGFR with EGFR-TKI-sensitizing and T790M mutations, acquired resistance to third-generation EGFR-TKIs invariably develops. Methods: Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M-mutated NSCLC patient who had progressed after a third-generation EGFR-TKI, TAS-121. EGFR-mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR-TKIs and a heat shock protein 90 (HSP90) inhibitor. Results: NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M-mutated cell line was sensitive to osimertinib or TAS-121 in vitro, EGFR-overexpressing cell lines displayed resistance to these EGFR-TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third-generation EGFR-TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines. Conclusions: EGFR amplification confers resistance to third-generation EGFR-TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification-mediated resistance.

Original languageEnglish
Pages (from-to)631-642
Number of pages12
JournalThoracic Cancer
Volume12
Issue number5
DOIs
Publication statusPublished - 2021 Mar

Keywords

  • acquired resistance
  • and heat shock protein 90
  • epidermal growth factor receptor
  • epidermal growth factor receptor amplification
  • epidermal growth factor receptor-tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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