Association of amphiregulin with the cetuximab sensitivity of gastric cancer cell lines

Int J Oncol. 2012 Aug;41(2):733-44. doi: 10.3892/ijo.2012.1479. Epub 2012 May 14.


The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated in clinical studies. Reliable biomarkers for the identification of patients who are likely to benefit from this treatment are not available. In this study, we assessed the activity of cetuximab in five gastric cancer cell lines (AGS, AZ521, Hs746T, LMSU and MKN1). The viability of two of these cell lines, AZ521 and MKN1, was significantly reduced by cetuximab treatment. High expression and secretion levels of the EGFR-binding ligand, amphiregulin (AREG), were associated with cetuximab responsiveness. MET activation and mutations in Kirsten-Ras gene (KRAS) were associated with cetuximab resistance. By introducing a hierarchy between these markers, we established a model that facilitated the correct classification of all five gastric cancer cell lines as cetuximab responsive or non-responsive. The highest priority was allocated to activating KRAS mutations, followed by MET activation and finally by the levels of secreted AREG. In order to validate these results, we used three additional human gastric cancer cell lines (KATOIII, MKN28 and MKN45). In conclusion, we propose that our model allows the response of gastric cancer cell lines to cetuximab treatment to be predicted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphiregulin
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor / drug effects
  • Cell Proliferation
  • Cell Survival / drug effects
  • Cetuximab
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm
  • EGF Family of Proteins
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / metabolism
  • Glycoproteins / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mutation
  • Phosphorylation
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Stomach Neoplasms / drug therapy*
  • ras Proteins / genetics


  • AREG protein, human
  • Amphiregulin
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • EGF Family of Proteins
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Epidermal Growth Factor
  • ErbB Receptors
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Cetuximab