生物谷报道：美国礼来公司（Eli Lilly and Company）和翻译基因组学研究院（the Translational Genomics Research institute）研究人员日前宣布，他们在乳腺癌、结肠癌和卵巢癌中发现一种AKT1基因复发突变（recurring mutation，生物谷编者译），这种突变AKT1基因诱导肿瘤细胞增殖，并帮助癌细胞抵抗某些治疗剂。相关文章刊登于Nature杂志。
PI3-激酶/AKT途径是人类肿瘤中最为活跃的细胞途径之一，导致癌细胞的生存和增长，途径中的许多成分是新药研发的候选靶标。AKT1是该途径的活性中心，在癌症中是联系上游突变调控蛋白和下游存活信号途径蛋白的中间环节。此次研究人员首次在在癌症患者的临床样本中发现AKT1直接突变，还未经细胞检测。
这项发现可以说是癌症生物学中具有启示意义的一个发现，证实AKT1是乳腺癌、结肠癌和卵巢癌的致癌基因。礼来公司Kerry L. Blanchard博士说，突变改变了PH（Pleckstrin同源序列，酶与细胞膜上的磷脂结合的部分）区中结合袋（binding pocket）的静电学特征。研究人员分析了包括乳腺癌、结肠癌和卵巢癌在内的共150个肿瘤样本。数据分析结果显示，8％的乳腺癌、6％的结肠癌和2％的卵巢癌的样本中，AKT1发生突变。
这是一个引人注目的研究，利用一系列久经考验的技术发现肿瘤基因组加工过程的新问题。James E. Thomas博士解释说，AKT1是一种蛋白激酶，在细胞生存、增殖和代谢活动中发挥重要作用。有趣的是，其它调控这些网络的蛋白在肺癌、前列腺癌、结肠癌和脑癌中也有突变现象。AKT1中的这种突变明显证实AKT1与癌症形成有关。
鉴定AKT1突变是礼来公司和TGen共同努力的结果。这项发现证实，临床水平（非依赖于模型系统）研究癌症遗传学的重要性。
原始出处:
Nature advance online publication 4 July 2007 | doi:10.1038/nature05933; Received 8 March 2007; Accepted 11 May 2007; Published online 4 July 2007
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer
John D. Carpten1, Andrew L. Faber2, Candice Horn2, Gregory P. Donoho2, Stephen L. Briggs3, Christiane M. Robbins1, Galen Hostetter1, Sophie Boguslawski2, Tracy Y. Moses1, Stephanie Savage1, Mark Uhlik2, Aimin Lin4, Jian Du2, Yue-Wei Qian4, Douglas J. Zeckner2, Greg Tucker-Kellogg5, Jeffrey Touchman1, Ketan Patel5, Spyro Mousses6, Michael Bittner1, Richard Schevitz3, Mei-Huei T. Lai2, Kerry L. Blanchard2 & James E. Thomas2
Division of Integrated Cancer Genomics, Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA
Cancer Discovery Research,
Global Structural Biology,
Integrative Biology, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA
Lilly Singapore Centre for Drug Discovery, 1 Science Park Road 04-01, The Capricorn, Singapore Science Park II, 117528 Singapore
Pharmaceutical Genomics, Translational Genomics Research Institute, TGen Suite 110, 13208 E. Shea Boulevard, Scottsdale, Arizona 85259, USA
Correspondence to: Kerry L. Blanchard2James E. Thomas2 Correspondence and requests for materials should be addressed to K.L.B. (Email: kblanc@lilly.com) or J.E.T. (Email: thomas_james_e@lilly.com).
Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.
