Gefitinib (IRESSA) sensitive lung cancer cell lines show phosphorylation of Akt without ligand stimulation

BMC Cancer. 2006 Dec 6;6:277. doi: 10.1186/1471-2407-6-277.

Abstract

Background: Phase III trials evaluating the efficacy of gefitinib (IRESSA) in non-small cell lung cancer (NSCLC) lend support to the need for improved patient selection in terms of gefitinib use. Mutation of the epidermal growth factor receptor (EGFR) gene is reported to be associated with clinical responsiveness to gefitinib. However, gefitinib-sensitive and prolonged stable-disease-defined tumors without EGFR gene mutation have also been reported.

Methods: To identify other key factors involved in gefitinib sensitivity, we analyzed the protein expression of molecules within the EGFR family, PI3K-Akt and Ras/MEK/Erk pathways and examined the sensitivity to gefitinib using the MTT cell proliferation assay in 23 lung cancer cell lines.

Results: We identified one highly sensitive cell line (PC9), eight cell lines displaying intermediate-sensitivity, and 14 resistant cell lines. Only PC9 and PC14 (intermediate-sensitivity) displayed an EGFR gene mutation including amplification. Eight out of the nine cell lines showing sensitivity had Akt phosphorylation without ligand stimulation, while only three out of the 14 resistant lines displayed this characteristic (P = 0.0059). Furthermore, the ratio of phosphor-Akt/total Akt in sensitive cells was higher than that observed in resistant cells (P = 0.0016). Akt phosphorylation was partially inhibited by gefitinib in all sensitive cell lines.

Conclusion: These results suggest that Akt phosphorylation without ligand stimulation may play a key signaling role in gefitinib sensitivity, especially intermediate-sensitivity. In addition, expression analyses of the EGFR family, EGFR gene mutation, and FISH (fluorescence in situ hybridization) analyses showed that the phosphorylated state of EGFR and Akt might be a useful clinical marker of Akt activation without ligand stimulation, in addition to EGFR gene mutation and amplification, particularly in adenocarcinomas.

Publication types

  • Comparative Study

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gefitinib
  • Gene Expression Regulation, Neoplastic
  • Genes, ras
  • Humans
  • In Situ Hybridization, Fluorescence
  • Ligands
  • Lung Neoplasms / drug therapy*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-3 / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Ligands
  • Quinazolines
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Gefitinib