ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines.
作者： J. A. Engelman , P. A. Janne , C. Mermel , J. Pearlberg , T. Mukohara
关键词: Receptor 、 Intracellular 、 Gefitinib 、 Biology 、 Molecular biology 、 Protein kinase B 、 Cell culture 、 ErbB 、 PI3K/AKT/mTOR pathway 、 Small hairpin RNA
摘要: Therapies that target the EGF receptor (EGFR), such as gefitinib (IRESSA), are effective in a subset of patients with advanced non-small cell lung cancer (NSCLC). The differences intracellular signaling networks between gefitinib-sensitive and -resistant NSCLCs remain poorly understood. In this study, we observe reduces phospho-Akt levels only NSCLC lines which it inhibits growth. To elucidate mechanism underlying observation, compared immunoprecipitates phosphoinositide 3-kinase (PI3K) lines. We PI3K associates ErbB-3 exclusively Gefitinib dissociates complex, thereby linking EGFR inhibition to decreased Akt activity. contrast, gefitinib-resistant cells do not use activate PI3K/Akt pathway. fact, abundant expression is detected Two endogenous distinct activating mutations (L858R Del747-749), frequently observed who respond gefitinib, also couple PI3K. Down-regulation by means short hairpin RNA leads lines, Calu-3 (WT EGFR) H3255 EGFR), but has no effect on activation A549 H522. conclude used pathway harboring WT mutant EGFRs.
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