Aberrant activations of cellular kinases and exploration of novel targeted therapy in human solid cancers

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In lung carcinomas and soft tissue sarcomas, Akt expression/activation, and AKT1-3 gene gains were investigated. In lung carcinomas, immunohistochemistry revealed expression of Akt in 60% and phosphorylated-Akt (p-Akt), Akt1, Akt2 in 40%, but expression of Akt3 was lower as 20% in approximate. A significant correlation between Akt2/p-Akt expression and lymph node metastasis was observed. In sarcomas, the cases showing activated Akt/mTOR pathway revealed worse prognosis in several histological types. FISH analysis indicated "FISH-positive" gene gain (amplification/high level polysomy) of AKT1/2 in 15 to 25% in both tumors. FISH-positive AKTs gene gain accompanied activation of Akt, but not EGFR gains. Microarray analysis revealed that AKT1/2 gene increase induced specific mRNA and microRNA, which are known to be involved in invasion or epithelial-mesenchymal transition. Moreover, a polymorphic site in AKT1 related to cancer predisposition was identified by SNP analysis.