Molecular alterations in AKT and its protein activation in human lung carcinomas

To evaluate the involvement of aberrant Akt in lung carcinomas, the frequency of Akt overexpression/activation and gene gains of AKT1 and AKT2 were investigated. Immunohistochemistry in 135 cases revealed overexpression of total-Akt in 62% and phosphorylated-Akt in 44%. A statistically significant correlation between Akt activation and lymph node metastasis was observed. Immunoblot analyses revealed almost consistent results. Fluorescence in situ hybridization for AKT1 and AKT2 genes in 62 carcinomas exhibiting total-Akt overexpression indicated amplification of AKT1 in 6.5% of total-Akt expressing cases (3.5% of total cases) and AKT1 gain by polysomy of chromosome 14 in 40% (high level in 8% and low level in 32%). For AKT2, amplification was observed in 6.5% of total-Akt expressing cases (3.5% of total cases) and polysomy of chromosome 19 in 44% (high level in 16% and low level in 28%). Total-Akt overexpression and fluorescence in situ hybridization positive gene gain (defined as amplification/high level polysomy) of AKT2 were more prevalent in small cell carcinoma. However, Akt activation and fluorescence in situ hybridization positive AKT1 gene gain were most frequent in large cell carcinoma. Fluorescence in situ hybridization positive AKTs gene gain accompanied overexpression/activation of Akt and all fluorescence in situ hybridization positive carcinomas harbored wild-type EGFR in disomy in this sample group examined; therefore, fluorescence in situ hybridization positive gene gains of AKTs versus EGFR or EGFR mutation occurred in a reciprocal manner. In conclusion, amplification of AKT1 and/or AKT2 and high-level polysomy were found in 16% of total cases, and this defined subset was characterized by the overexpression/activation of Akt, reciprocal to EGFR aberrations. Thus, novel Akt-targeted therapy could be applicable for this particular group of carcinomas in which Akt may be critically involved. (C) 2012 Elsevier Inc. All rights reserved.