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

在肺癌和软组织肉瘤中，研究Akt的表达/激活和AKT1-3基因的获得。在肺癌组织中，Akt的表达为60%，磷酸化Akt(p-Akt)、Akt1、Akt2的表达为40%，而AKT3的表达较低，约为20%。Akt2/p-Akt的表达与淋巴结转移密切相关。在肉瘤中，Akt/mTOR通路激活的病例在几种组织学类型中预后较差。FISH分析显示，在这两种肿瘤中，AKT1/2的FISH阳性基因增加(扩增/高水平多倍体)的比例为15%至25%。FISH阳性的AKTS基因的获得伴随着Akt的激活，而不是EGFR的获得。基因芯片分析显示，AKT1/2基因上调诱导了特异的mRNA和microRNA，它们被认为参与了侵袭或上皮-间充质转化。此外，SNP分析还发现了AKT1基因中一个与肿瘤易感性相关的多态位点。

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.