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Paradigm of kinase-driven pathway downstream of epidermal growth factor receptor/Akt in human lung carcinomas

Yoh Dobashi1, Shioto Suzuki, Maiko Kimura

  • 1Department of Pathology, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan. ydobashi@omiya.jichi.ac.jp

Human Pathology
|November 3, 2010
PubMed

Insights

Epidermal Growth Factor Receptor (EGFR) pathway activation is common in non-small cell lung cancer (NSCLC). This pathway, including Akt and mTOR, is linked to tumor growth and metastasis, offering potential therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal Growth Factor Receptor (EGFR) signaling plays a crucial role in cell proliferation and survival.
  • Dysregulation of EGFR and its downstream pathways are implicated in various cancers, including lung carcinoma.
  • Understanding the activation status of EGFR and its downstream effectors is vital for targeted therapy development.

Purpose of the Study:

  • To analyze the expression and activation of EGFR and its downstream proteins (Akt, mTOR, S6K, rS6, 4E-BP1) in lung carcinomas.
  • To evaluate the correlation between EGFR activation and the phosphorylation status of downstream signaling molecules.
  • To investigate the clinical significance of EGFR/Akt/mTOR pathway activation in non-small cell lung carcinomas (NSCLCs).

Main Methods:

  • Immunohistochemical analysis of 140 lung carcinoma cases to assess EGFR expression and phosphorylation.
  • Immunoblotting to analyze the activation status of downstream signaling proteins.
  • Clinicopathologic analysis to correlate protein activation with clinical parameters like lymph node metastasis.

Main Results:

  • EGFR overexpression and phosphorylation were observed in 37.9% and 37.1% of cases, respectively, with lower prevalence in small cell carcinoma.
  • Upon EGFR activation, at least one of the mTOR/S6K or mTOR/4E-BP1 cascades was activated in 60% of cases.
  • Constitutive activation of the EGFR-Akt-mTOR pathway was found in 17.9% of NSCLCs, with varying frequencies among histologic types.
  • In adenocarcinoma, 90% showed mTOR activation, and 60% of these had downstream S6K/rS6 activation.
  • EGFR mutations were frequently associated with EGFR phosphorylation and constitutive activation of the entire pathway through rS6 in 50% of mutated cases.
  • Akt activation correlated with lymph node metastasis, while rS6 and mTOR activation were specifically linked to nodal metastasis in adenocarcinoma and squamous cell carcinoma, respectively.

Conclusions:

  • Constitutive activation of the EGFR/Akt/mTOR pathway occurs in a subset of NSCLCs.
  • The mTOR/S6K/rS6 axis is frequently activated in adenocarcinoma and can be activated by EGFR mutations in squamous cell carcinoma.
  • mTOR and rS6 may serve as determinants of nodal metastasis in squamous cell carcinoma and adenocarcinoma, respectively, highlighting their potential as therapeutic targets.

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