ErbB-3 Mediates Phosphoinositide 3-Kinase Activity in Gefitinib-Sensitive Non-Small Cell Lung Cancer Cell Lines

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 10; pp. 3788 - 3793
• Main Authors: Engelman, Jeffrey A., Jänne, Pasi A., Mermel, Craig, Pearlberg, Joseph, Mukohara, Toru, Fleet, Christina, Cichowski, Karen, Johnson, Bruce E., Cantley, Lewis C.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.03.2005; National Acad Sciences
• Subjects: Animals; Antibodies; Antineoplastic Agents - pharmacology; Biological Sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell growth; Cell Line, Tumor; Cell lines; CHO Cells; Comparative analysis; Cricetinae; Enzymes; Humans; Lung cancer; Lung neoplasms; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical research; Medical schools; Mutation; NIH 3T3 cells; Pharmacology; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-akt; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - physiology; Receptor, ErbB-3 - physiology; Receptors; Tumor cell line
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0409773102

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 in intracellular signaling networks between gefitinib-sensitive and -resistant NSCLCs remain poorly understood. In this study, we observe that gefitinib reduces phospho-Akt levels only in NSCLC cell lines in which it inhibits growth. To elucidate the mechanism underlying this observation, we compared immunoprecipitates of phosphoinositide 3-kinase (PI3K) between gefitinib-sensitive and -resistant NSCLC cell lines. We observe that PI3K associates with ErbB-3 exclusively in gefitinib-sensitive NSCLC cell lines. Gefitinib dissociates this complex, thereby linking EGFR inhibition to decreased Akt activity. In contrast, gefitinib-resistant cells do not use ErbB-3 to activate the PI3K/Akt pathway. In fact, abundant ErbB-3 expression is detected only in gefitinib-sensitive NSCLC cell lines. Two gefitinib-sensitive NSCLC cell lines with endogenous distinct activating EGFR mutations (L858R and Del747-749), frequently observed in NSCLC patients who respond to gefitinib, also use ErbB-3 to couple to PI3K. Down-regulation of ErbB-3 by means of short hairpin RNA leads to decreased phospho-Akt levels in the gefitinib-sensitive NSCLC cell lines, Calu-3 (WT EGFR) and H3255 (L858R EGFR), but has no effect on Akt activation in the gefitinib-resistant cell lines, A549 and H522. We conclude that ErbB-3 is used to couple EGFR to the PI3K/Akt pathway in gefitinib-sensitive NSCLC cell lines harboring WT and mutant EGFRs.