JUN-Mediated Downregulation of EGFR Signaling Is Associated with Resistance to Gefitinib in EGFR-mutant NSCLC Cell Lines

Mol Cancer Ther. 2017 Aug;16(8):1645-1657. doi: 10.1158/1535-7163.MCT-16-0564. Epub 2017 May 31.

Abstract

Mutations or deletions in exons 18-21 in the EGFR) are present in approximately 15% of tumors in patients with non-small cell lung cancer (NSCLC). They lead to activation of the EGFR kinase domain and sensitivity to molecularly targeted therapeutics aimed at this domain (gefitinib or erlotinib). These drugs have demonstrated objective clinical response in many of these patients; however, invariably, all patients acquire resistance. To examine the molecular origins of resistance, we derived a set of gefitinib-resistant cells by exposing lung adenocarcinoma cell line, HCC827, with an activating mutation in the EGFR tyrosine kinase domain, to increasing gefitinib concentrations. Gefitinib-resistant cells acquired an increased expression and activation of JUN, a known oncogene involved in cancer progression. Ectopic overexpression of JUN in HCC827 cells increased gefitinib IC50 from 49 nmol/L to 8 μmol/L (P < 0.001). Downregulation of JUN expression through shRNA resensitized HCC827 cells to gefitinib (IC50 from 49 nmol/L to 2 nmol/L; P < 0.01). Inhibitors targeting JUN were 3-fold more effective in the gefitinib-resistant cells than in the parental cell line (P < 0.01). Analysis of gene expression in patient tumors with EGFR-activating mutations and poor response to erlotinib revealed a similar pattern as the top 260 differentially expressed genes in the gefitinib-resistant cells (Spearman correlation coefficient of 0.78, P < 0.01). These findings suggest that increased JUN expression and activity may contribute to gefitinib resistance in NSCLC and that JUN pathway therapeutics merit investigation as an alternate treatment strategy. Mol Cancer Ther; 16(8); 1645-57. ©2017 AACR.

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Down-Regulation* / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • ErbB Receptors / metabolism*
  • Gefitinib
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Mutation / genetics
  • Phenotype
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Proteomics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • Signal Transduction* / drug effects
  • Up-Regulation / drug effects

Substances

  • Chromatin
  • Proto-Oncogene Proteins c-jun
  • Quinazolines
  • ErbB Receptors
  • Gefitinib