Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance.
Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance.
复制标题
磷脂酰肌醇-3-激酶途径的突变预测抑制剂PX-866的抗肿瘤活性，而致癌性RAS是耐药性的主要预测指标。
DOI：
10.1158/0008-5472.can-07-6656
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发表时间：
2009-01-01
期刊：
影响因子：
11.2
通讯作者：
Powis G
中科院分区：
文献类型：
--
作者：
Ihle NT;Lemos R Jr;Wipf P;Yacoub A;Mitchell C;Siwak D;Mills GB;Dent P;Kirkpatrick DL;Powis G
针对源自不同组织来源的细胞系的13种实验性人类肿瘤异种移植物测试了新型磷脂酰肌醇-3-激酶（PI-3-激酶）抑制剂PX-866。突变的PI-3-激酶（PIK 3CA）和PTEN活性的丧失是足够的，但不是必要的预测敏感性的PI-3-K抑制剂PX-866的抗肿瘤活性的存在下，野生型Ras，而突变的致癌Ras是一个主要的决定因素的电阻，即使在肿瘤与共存的突变PIK 3CA。通过肿瘤磷酸-Ser 473-Akt测量的PI-3-激酶信号传导的活化水平不足以预测对PX-866的体内抗肿瘤应答。反相蛋白质阵列（RPPA）结果显示，在PX-866耐药的细胞系中，Ras依赖的下游靶点c-Myc和cyclin B表达升高。使用H-Ras构建体组成性地和优先地激活Ras的三个最佳定义的下游靶标，即Raf、RalGDS和PI-3-激酶的研究表明，突变型Ras通过其利用多种肿瘤发生途径的能力来介导抗性。Ras和下游信号通路的识别驱动PI-3激酶抑制的耐药性可能作为一个重要的指导患者选择的抑制剂进入临床试验，并与其他分子靶向药物的合理组合的发展。
The novel phosphatidylinositol-3-kinase (PI-3-kinase) inhibitor PX-866 was tested against 13 experimental human tumor xenografts derived from cell lines of various tissue origins. Mutant PI-3-kinase (PIK3CA) and loss of PTEN activity were sufficient but not necessary as predictors of sensitivity to the antitumor activity of the PI-3-K inhibitor PX-866 in the presence of wild type Ras, while mutant oncogenic Ras was a dominant determinant of resistance, even in tumors with coexisting mutations in PIK3CA. The level of activation of PI-3-kinase signaling measured by tumor phospho-Ser473-Akt was insufficient to predict in vivo antitumor response to PX-866. Reverse phase protein array (RPPA) revealed that the Ras dependent down stream targets c-Myc and cyclin B were elevated in cell lines resistant to PX-866 in vivo. Studies using an H-Ras construct to constitutively and preferentially activate the three best defined downstream targets of Ras, namely Raf, RalGDS, and PI-3-kinase, showed that mutant Ras mediates resistance through its ability to utilize multiple pathways for tumorigenesis. The identification of Ras and downstream signaling pathways driving resistance to PI-3-kinase inhibition may serve as an important guide for patient selection as inhibitors enter clinical trials, and for the development of rational combinations with other molecularly targeted agents.