Lack of AKT activation in lung cancer cells with EGFR mutation is a novel marker of cetuximab sensitivity.

Abstract

Epidermal growth factor receptor (EGFR) mutation is the best marker of sensitivity to the EGFR tyrosine kinase inhibitor gefitinib, but a marker for the anti-EGFR antibody cetuximab has not been identified in lung cancer. The present study investigated markers for sensitivity to cetuximab. Sensitivity to cetuximab and gefitinib was compared with EGFR expression, EGFR and KRAS mutation, and EGFR gene copy numbers in lung cancer cell lines. We also studied the effect of these agents on the activation of EGFR, ERK, AKT, and STAT3 in cetuximab-sensitive and -resistant cell lines. We found one cetuximab-sensitive cell line with EGFR mutation among 19 lung cancer cell lines. Analysis of molecules downstream from EGFR revealed that AKT phosphorylation was suppressed in this cell line. Augmentation of AKT phosphorylation by transfection of a plasmid induced resistance to cetuximab. Acquisition of cetuximab resistance was associated with AKT activation in this cell line, while pharmacological inhibition of AKT markedly enhanced the growth inhibitory effect of cetuximab. Dephosphorylation of AKT in association with EGFR mutation is a candidate marker for sensitivity to cetuximab, and combined use of an AKT pathway inhibitor with cetuximab could be a novel therapeutic strategy for lung cancer.

• Authors: Miyako Takata, Hiroki Chikumi, Naomi Miyake, Kaori Adachi, Yasunobu Kanamori, Akira Yamasaki, Tadashi Igishi, Naoto Burioka, Eiji Nanba, Eiji Shimizu
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 13 Issue 6 Pg. 369-78 (Apr 2012) ISSN: 1555-8576 [Electronic] United States
• PMID: 22313637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Biomarkers, Tumor
• Quinazolines
• STAT3 Transcription Factor
• STAT3 protein, human
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• Cetuximab
• Gefitinib

Topics

• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Cell Line, Tumor
• Cetuximab
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics)
• Gefitinib
• Gene Dosage
• Genes, ras
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Mutation
• Phosphorylation
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Quinazolines (pharmacology)
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction (drug effects)