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

Jeffrey A Engelman1, Pasi A Jänne, Craig Mermel

  • 1Department of Systems Biology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 26, 2005
PubMed

Insights

Gefitinib (IRESSA) is effective in some non-small cell lung cancers (NSCLC) by inhibiting the epidermal growth factor receptor (EGFR). This study reveals that ErbB-3 is crucial for linking EGFR to the PI3K/Akt pathway in gefitinib-sensitive NSCLC, explaining treatment response differences.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Targeted therapies like gefitinib (IRESSA) show efficacy in a subset of advanced non-small cell lung cancer (NSCLC) patients.
  • The molecular mechanisms differentiating gefitinib-sensitive and -resistant NSCLCs are not fully understood.
  • Understanding these differences is key to improving patient stratification and treatment strategies.

Purpose of the Study:

  • To investigate the intracellular signaling pathways affected by gefitinib in NSCLC.
  • To identify the molecular components responsible for gefitinib sensitivity or resistance.
  • To elucidate the role of ErbB-3 in the phosphoinositide 3-kinase (PI3K)/Akt pathway activation in NSCLC.

Main Methods:

  • Comparison of immunoprecipitates of phosphoinositide 3-kinase (PI3K) between gefitinib-sensitive and -resistant NSCLC cell lines.
  • Assessment of the association between PI3K and ErbB-3 in response to gefitinib.
  • Analysis of phospho-Akt levels following gefitinib treatment and ErbB-3 down-regulation using short hairpin RNA (shRNA).

Main Results:

  • Gefitinib reduced phospho-Akt levels only in growth-inhibited NSCLC cell lines.
  • PI3K associated with ErbB-3 exclusively in gefitinib-sensitive NSCLC cell lines, and gefitinib disrupted this complex.
  • ErbB-3 expression was abundant in gefitinib-sensitive cells and essential for coupling epidermal growth factor receptor (EGFR) to the PI3K/Akt pathway, irrespective of EGFR mutation status (L858R, Del747-749, or wild-type).

Conclusions:

  • ErbB-3 acts as a critical mediator connecting EGFR to PI3K/Akt signaling in gefitinib-sensitive NSCLC.
  • The reliance on ErbB-3 for PI3K/Akt activation distinguishes sensitive from resistant NSCLC phenotypes.
  • Targeting the EGFR-ErbB-3-PI3K/Akt axis may offer therapeutic strategies for NSCLC patients responding to gefitinib.

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