論文

査読有り
2012年10月

HER2 Amplification: A Potential Mechanism of Acquired Resistance to EGFR Inhibition in EGFR-Mutant Lung Cancers That Lack the Second-Site EGFR(T790M) Mutation

CANCER DISCOVERY
  • Ken Takezawa
  • Valentina Pirazzoli
  • Maria E. Arcila
  • Caroline A. Nebhan
  • Xiaoling Song
  • Elisa de Stanchina
  • Kadoaki Ohashi
  • Yelena Y. Janjigian
  • Paula J. Spitzler
  • Mary Ann Melnick
  • Greg J. Riely
  • Mark G. Kris
  • Vincent A. Miller
  • Marc Ladanyi
  • Katerina Politi
  • William Pao
  • 全て表示

2
10
開始ページ
922
終了ページ
933
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/2159-8290.CD-12-0108
出版者・発行元
AMER ASSOC CANCER RESEARCH

EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR(T790M) were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.

リンク情報
DOI
https://doi.org/10.1158/2159-8290.CD-12-0108
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/22956644
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473100
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000311904000024&DestApp=WOS_CPL
URL
http://europepmc.org/abstract/med/22956644
URL
http://orcid.org/0000-0002-5180-3933
ID情報
  • DOI : 10.1158/2159-8290.CD-12-0108
  • ISSN : 2159-8274
  • ORCIDのPut Code : 49906291
  • PubMed ID : 22956644
  • PubMed Central 記事ID : PMC3473100
  • Web of Science ID : WOS:000311904000024

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