Mechanisms and overcome of acquired resistance to EGFR tyrosine kinase inhibitors

Junichi Soh, Shinichi Toyooka, Tsuyoshi Ueno, Shinichiro Miyoshi

Research output: Contribution to journalReview article

Abstract

Development of effective therapies for non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, which account for approximately 40% of lung adenocarcinoma patients in Japan, is important to improve the clinical outcome of NSCLC. EGFR-mutant NSCLCs are sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and elucidating the binding affinity of adenosine triphosphate (ATP) and EGFR-TKI to wild type or mutant EGFR helps our understanding of the mechanisms of resistance to EGFR-TKI. The mechanisms of acquired resistance to EGFR-TKIs are broadly classified into two categories: 1) secondly acquired EGFR mutations including T790M and 2) "oncogene kinase switch" such as MET gene amplification. To overcome the acquired resistance, it is essential to develop new drugs and therapeutic strategies. The heat shock protein 90 (Hsp90) inhibitors show anti-proliferative effect by inhibiting the stabilization of various client proteins such as mutant-EGFR, MET and AKT. The clinical trials of Hsp90 inhibitors are currently-conducted, which is expected to show the efficacy on NSCLC patients with any kind of acquired resistance for EGFR-TKIs.

Original languageEnglish
Pages (from-to)131-135
Number of pages5
JournalJapanese Journal of Lung Cancer
Volume52
Issue number2
DOIs
Publication statusPublished - Apr 2012

Keywords

  • ATP
  • Acquired resistance
  • EGFR-TKI
  • Hsp90 inhibitor
  • T790M mutation

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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