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ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Jänne, Pasi Antero Mermel, Craig Pearlberg, Joseph Mukohara, Toru Fleet, Christina M. Cichowski, Karen Johnson, Bruce Evan |
| Copyright Year | 2005 |
| Abstract | 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. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.pnas.org/content/102/10/3788.full.pdf |
| PubMed reference number | 15731348v1 |
| Volume Number | 102 |
| Issue Number | 10 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 1-Phosphatidylinositol 3-Kinase 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase Cultured Cell Line EGFR protein, human Iressa Mutation Non-Small Cell Lung Carcinoma Patients Phosphatidylinositols Proto-Oncogene Proteins c-akt Short Hairpin RNA Small cell carcinoma of lung cancer cell gefitinib phosphatidylinositol 3-kinase activity |
| Content Type | Text |
| Resource Type | Article |
