| RRC ID |
68836
|
| 著者 |
Takata M, Chikumi H, Miyake N, Adachi K, Kanamori Y, Yamasaki A, Igishi T, Burioka N, Nanba E, Shimizu E.
|
| タイトル |
Lack of AKT activation in lung cancer cells with EGFR mutation is a novel marker of cetuximab sensitivity.
|
| ジャーナル |
Cancer Biol Ther
|
| 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.
|
| 巻・号 |
13(6)
|
| ページ |
369-78
|
| 公開日 |
2012-4-1
|
| DOI |
10.4161/cbt.19238
|
| PII |
19238
|
| PMID |
22313637
|
| MeSH |
Antibodies, Monoclonal / pharmacology*
Antibodies, Monoclonal, Humanized
Antineoplastic Agents / pharmacology*
Biomarkers, Tumor / genetics
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / genetics*
Cell Line, Tumor
Cetuximab
Drug Resistance, Neoplasm / genetics
ErbB Receptors / genetics*
Gefitinib
Gene Dosage
Genes, ras
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Mutation
Phosphorylation
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism*
Quinazolines / pharmacology
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects
|
| IF |
3.659
|
| リソース情報 |
| ヒト・動物細胞 |
PC-9(RCB4455) |
