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Research Article

ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines

Jeffrey A. Engelman, Pasi A. Jänne, Craig Mermel, Joseph Pearlberg, Toru Mukohara, Christina Fleet, Karen Cichowski, Bruce E. Johnson, and Lewis C. Cantley
PNAS March 8, 2005 102 (10) 3788-3793; https://doi.org/10.1073/pnas.0409773102
Jeffrey A. Engelman
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Pasi A. Jänne
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Craig Mermel
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Joseph Pearlberg
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Toru Mukohara
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Christina Fleet
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Karen Cichowski
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Bruce E. Johnson
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Lewis C. Cantley
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  1. Contributed by Lewis C. Cantley, December 27, 2004

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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.

  • Akt
  • EGF receptor

Footnotes

  • ↵ ¶ 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.

  • 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.

  • 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
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ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines
Jeffrey A. Engelman, Pasi A. Jänne, Craig Mermel, Joseph Pearlberg, Toru Mukohara, Christina Fleet, Karen Cichowski, Bruce E. Johnson, Lewis C. Cantley
Proceedings of the National Academy of Sciences Mar 2005, 102 (10) 3788-3793; DOI: 10.1073/pnas.0409773102

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ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines
Jeffrey A. Engelman, Pasi A. Jänne, Craig Mermel, Joseph Pearlberg, Toru Mukohara, Christina Fleet, Karen Cichowski, Bruce E. Johnson, Lewis C. Cantley
Proceedings of the National Academy of Sciences Mar 2005, 102 (10) 3788-3793; DOI: 10.1073/pnas.0409773102
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Proceedings of the National Academy of Sciences of the United States of America: 102 (10)
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