PMID- 17150102 OWN - NLM STAT- MEDLINE DCOM- 20070201 LR - 20181201 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 6 DP - 2006 Dec 6 TI - Gefitinib (IRESSA) sensitive lung cancer cell lines show phosphorylation of Akt without ligand stimulation. PG - 277 AB - 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. FAU - Noro, Rintaro AU - Noro R AD - Department of Pulmonary Medicine/Infection and Oncology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. r-noro@nms.ac.jp FAU - Gemma, Akihiko AU - Gemma A FAU - Kosaihira, Seiji AU - Kosaihira S FAU - Kokubo, Yutaka AU - Kokubo Y FAU - Chen, Mingwei AU - Chen M FAU - Seike, Masahiro AU - Seike M FAU - Kataoka, Kiyoko AU - Kataoka K FAU - Matsuda, Kuniko AU - Matsuda K FAU - Okano, Tetsuya AU - Okano T FAU - Minegishi, Yuji AU - Minegishi Y FAU - Yoshimura, Akinobu AU - Yoshimura A FAU - Kudoh, Shoji AU - Kudoh S LA - eng PT - Comparative Study PT - Journal Article DEP - 20061206 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Antineoplastic Agents) RN - 0 (Ligands) RN - 0 (Quinazolines) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) RN - S65743JHBS (Gefitinib) SB - IM MH - Antineoplastic Agents/pharmacology/therapeutic use MH - Carcinoma, Non-Small-Cell Lung/*drug therapy MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - DNA Mutational Analysis MH - Drug Resistance, Neoplasm MH - Enzyme Activation MH - ErbB Receptors/genetics/metabolism MH - Gefitinib MH - Gene Expression Regulation, Neoplastic MH - Genes, ras MH - Humans MH - In Situ Hybridization, Fluorescence MH - Ligands MH - Lung Neoplasms/*drug therapy MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - PTEN Phosphohydrolase/metabolism MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Quinazolines/*pharmacology/therapeutic use MH - Receptor, ErbB-2/metabolism MH - Receptor, ErbB-3/metabolism MH - p38 Mitogen-Activated Protein Kinases/metabolism PMC - PMC1698934 EDAT- 2006/12/08 09:00 MHDA- 2007/02/03 09:00 PMCR- 2006/12/06 CRDT- 2006/12/08 09:00 PHST- 2006/06/08 00:00 [received] PHST- 2006/12/06 00:00 [accepted] PHST- 2006/12/08 09:00 [pubmed] PHST- 2007/02/03 09:00 [medline] PHST- 2006/12/08 09:00 [entrez] PHST- 2006/12/06 00:00 [pmc-release] AID - 1471-2407-6-277 [pii] AID - 10.1186/1471-2407-6-277 [doi] PST - epublish SO - BMC Cancer. 2006 Dec 6;6:277. doi: 10.1186/1471-2407-6-277.