Genomic complexity and AKT dependence in serous ovarian cancer.
Genomic complexity and AKT dependence in serous ovarian cancer.
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DOI：
10.1158/2159-8290.cd-11-0170
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发表时间：
2012-01
期刊：
影响因子：
28.2
通讯作者：
Solit DB
中科院分区：
文献类型：
--
作者：
Hanrahan AJ;Schultz N;Westfal ML;Sakr RA;Giri DD;Scarperi S;Janakiraman M;Olvera N;Stevens EV;She QB;Aghajanian C;King TA;Stanchina Ed;Spriggs DR;Heguy A;Taylor BS;Sander C;Rosen N;Levine DA;Solit DB
尚未开发出针对卵巢癌的有效癌蛋白靶向疗法。为了探索PI 3激酶/AKT信号在这种疾病中的作用，我们对卵巢癌细胞系和肿瘤进行了遗传和功能分析。PI 3 K通路改变在两者中是常见的，但突变变化谱不同。该途径的遗传激活是必要的，但不足以赋予对AKT选择性抑制的敏感性，并且具有RAS途径改变或RB 1缺失的细胞对AKT抑制具有抗性，无论它们是否具有共存的PI 3 K/AKT途径激活。抑制AKT 1导致卵巢细胞系亚群的生长停滞，但在AKT 3表达的细胞系中则不然，这需要泛AKT抑制。因此，卵巢肿瘤的一个子集对AKT抑制敏感，但该疾病的遗传异质性表明，用AKT通路抑制剂进行有效治疗将需要对每个患者的肿瘤进行详细的分子分析。
Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of PI3 kinase/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3K pathway alterations were common in both, but the spectrum of mutational changes differed. Genetic activation of the pathway was necessary, but not sufficient, to confer sensitivity to selective inhibition of AKT and cells with RAS pathway alterations or RB1 loss were resistant to AKT inhibition, whether or not they had coexistent PI3K/AKT pathway activation. Inhibition of AKT1 caused growth arrest in a subset of ovarian cell lines, but not in those with AKT3 expression, which required pan-AKT inhibition. Thus, a subset of ovarian tumors are sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patient’s tumor.