HER2 amplification: A potential mechanism of acquired resistance to egfr inhibition in EGFR -mutant lung cancers that lack the second-site EGFR T790M mutation Academic Article uri icon

Overview

MeSH Major

  • Adenocarcinoma
  • Drug Resistance, Neoplasm
  • Lung Neoplasms
  • Receptor, Epidermal Growth Factor
  • Receptor, ErbB-2

abstract

  • 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.

publication date

  • October 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3473100

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-12-0108

PubMed ID

  • 22956644

Additional Document Info

start page

  • 922

end page

  • 33

volume

  • 2

number

  • 10