Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer Academic Article uri icon

Overview

MeSH Major

  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Epidermal Growth Factor

abstract

  • Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.

publication date

  • August 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3408577

Digital Object Identifier (DOI)

  • 10.1038/ng.2330

PubMed ID

  • 22751098

Additional Document Info

start page

  • 852

end page

  • 60

volume

  • 44

number

  • 8