論文 - 詳細
RRC ID | 42832 |
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著者 | Noro R, Gemma A, Kosaihira S, Kokubo Y, Chen M, Seike M, Kataoka K, Matsuda K, Okano T, Minegishi Y, Yoshimura A, Kudoh S. |
タイトル | Gefitinib (IRESSA) sensitive lung cancer cell lines show phosphorylation of Akt without ligand stimulation. |
ジャーナル | BMC Cancer |
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. |
巻・号 | 6 |
ページ | 277 |
公開日 | 2006-12-6 |
DOI | 10.1186/1471-2407-6-277 |
PII | 1471-2407-6-277 |
PMID | 17150102 |
PMC | PMC1698934 |
MeSH | 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 |
IF | 3.15 |
引用数 | 44 |
WOS 分野 | ONCOLOGY |
リソース情報 | |
ヒト・動物細胞 | RERF-LC-KJ(RCB1313) LC-1/sq(RCB0455) RERF-LC-AI(RCB0444) MS-1(RCB0725) |