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Contributed by Lewis C. Cantley, December 27, 2004
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.
Footnotes
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↵ ¶ To whom correspondence should be addressed at: Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Room 1022, Boston, MA 02115. E-mail: lewis_cantley{at}hms.harvard.edu.
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Author contributions: J.A.E., P.A.J., and L.C.C. designed research; J.A.E., C.M., T.M., and C.F. performed research; J.A.E., P.A.J., J.P., K.C. and B.E.J. contributed new reagents/analytic tools; J.A.E., P.A.J., B.E.J., and L.C.C. analyzed data; and J.A.E. and L.C.C. wrote the paper.
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Abbreviations: EGFR, EGF receptor; NSCLC, non-small cell lung cancer; PI3K, phosphoinositide 3-kinase; shRNA, short hairpin RNA; TKI, tyrosine kinase inhibitor; IPs, immunoprecipitates; PTyr, phosphotyrosine.
- Copyright © 2005, The National Academy of Sciences
ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines
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