AKT1E17K in human solid tumours
AKT1E17K in human solid tumours
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DOI：
10.1038/onc.2008.170
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发表时间：
2008-09-18
期刊：
影响因子：
8
通讯作者：
Bardelli, A.
中科院分区：
文献类型：
--
作者：
Bleeker, F. E.;Felicioni, L.;Bardelli, A.
丝氨酸-苏氨酸激酶 AKT1 是 PI3K 控制的致癌途径的核心参与者。最近，在乳腺癌、结直肠癌、肺癌和卵巢癌中检测到 AKT1 (E17K) 体细胞突变。 E17K 的变化导致 AKT1 的组成型激活并诱发小鼠白血病。我们确定了 764 个肿瘤样本中 E17K 变异的出现情况。这些包括乳腺癌、肺癌、卵巢癌、结直肠癌和胰腺癌以及黑色素瘤和胶质母细胞瘤。尽管已知这些肿瘤与 PI3K 信号通路相关的基因发生改变，但仅在乳腺癌 (16/273)、结直肠癌 (1/88) 和肺癌 (1/155) 中检测到 AKT1(E17K)。在乳腺起源的肿瘤中，AKT1(E17K) 变异与 PIK3CA(E454K)（或 H1047R）等位基因相互排斥，并且仅存在于导管和小叶组织型中。我们的结果表明 AKT1 突变似乎以组织特异性方式发生，具有基本和临床意义。首先，突变 AKT1 在致癌 PI3K 信号传导中的活性可能严格依赖于细胞和组织环境。其次，旨在选择性靶向 AKT1(E17K) 变体的治疗努力主要对特定癌症类型有效。
The serine- threonine kinase AKT1 is a central player in the oncogenic pathway controlled by PI3K. Recently, a somatic mutation in AKT1 (E17K) has been detected in breast, colorectal, lung and ovarian cancers. The E17K change results in constitutive AKT1 activation and induces leukaemia in mice. We determined the occurrence of the E17K variant in a panel of 764 tumour samples. These included breast, lung, ovarian, colorectal and pancreatic carcinomas as well as melanomas and glioblastomas. Despite the fact that these tumours are known to bear alterations in genes involved in the PI3K signalling pathway, AKT1(E17K) was detected only in breast (16/273), colorectal (1/88) and lung(1/155) cancers. Within the neoplasms of breast origin, the AKT1(E17K) variant was mutually exclusive with respect to the PIK3CA(E454K) (or H1047R) alleles and was present only in ductal and lobular histotypes. Our results, showing that AKT1 mutations seem to occur in a tissue-specific fashion have basic and clinical implications. First, the activity of mutated AKT1 in oncogenic PI3K signalling could be strictly dependent on the cell and tissue milieu. Second, therapeutic efforts aimed at selective targeting the AKT1(E17K) variant could be effective mainly in specific cancer types.