Paradigm of kinase-driven pathway downstream of epidermal growth factor receptor/Akt in human lung carcinomas.
The expression/activation of epidermal growth factor receptor (EGFR) and the correlation with the phosphorylation status of downstream modulator proteins, Akt, mammalian target of rapamycin (mTOR), p70S6-kinase (S6K), ribosomal protein S6 (rS6), and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), were analyzed and EGFR/Akt signaling was evaluated in lung carcinomas. Immunohistochemical analysis of 140 cases revealed overexpression of EGFR in 37.9% and phosphorylation in 37.1%, but much less in small cell carcinoma. Combined analysis with immunoblotting revealed that when EGFR is activated, at least one of the mTOR/S6K or mTOR/4E-BP1 cascades was activated in 60% of the cases. Furthermore, constitutive activation of EGFR-Akt-mTOR was found in 17.9% of nonsmall cell lung carcinomas (NSCLCs). For each protein, the frequencies of the activation vary among histologic types. In adenocarcinoma (AC), 90% revealed mTOR activation regardless of EGFR status, and 60% of these showed activation of downstream S6K/rS6. Furthermore, mutation of EGFR was frequently accompanied by phosphorylation of EGFR and constitutive activation of entire EGFR through rS6 was observed in 50% of carcinoma harboring EGFR mutation, including squamous cell carcinoma (SCC). By clinicopathologic analysis, Akt activation was correlated with lymph node metastasis in general, but nodal metastasis was correlated with rS6 activation in AC and with mTOR activation in SCC. In conclusion, (i) constitutive activation of EGFR/Akt/mTOR pathway was present in defined subset of NSCLC; (ii) mTOR/S6K/rS6 axis is frequently activated in AC, and constitutively activated through Akt by EGFR mutation even in SCC; and (iii) mTOR and rS6 are possible determinants of nodal metastasis in SCC and AC, respectively.
Department of Pathology, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan. ydobashi@omiya.jichi.ac.jp
Yoh
Y
Dobashi
Shioto
S
Suzuki
Maiko
M
Kimura
Hirochika
H
Matsubara
Hiroyoshi
H
Tsubochi
Issei
I
Imoto
Akishi
A
Ooi
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases