Systems Biology Reveals New Strategies for Personalizing Cancer Medicine and Confirms the Role of PTEN in Resistance to Trastuzumab
Systems Biology Reveals New Strategies for Personalizing Cancer Medicine and Confirms the Role of PTEN in Resistance to Trastuzumab
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DOI：
10.1158/0008-5472.can-09-0777
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发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Harrison, David J.
中科院分区：
文献类型：
--
作者：
Faratian, Dana;Goltsov, Alexey;Harrison, David J.
对曲妥珠单抗等靶向癌症治疗的耐药性是一个常见的临床问题，不仅因为HER2受体表达不足，还因为细胞信号通路的压倒一切的激活状态。系统生物学方法有助于快速对因素进行计算机测试，这可能会导致对靶向治疗的耐药性。在这项研究中，我们的目标是开发一种新的动力学模型，可以用来预测受体酪氨酸激酶(RTK)抑制剂治疗的耐药性，并直接在体外和临床样本中进行预测。新的数学模型包括RTK抑制剂抗体结合、HER2/HER3二聚化和抑制、AKT/丝裂原活化蛋白激酶的串扰以及PTEN的调节特性。该模型通过使用反相蛋白质微阵列从癌细胞系中获得的定量磷蛋白表达数据进行了参数化。定量的PTEN蛋白表达被发现是矽肺抵抗抗HER2治疗的关键决定因素，这预示着使用PTEN抑制剂BP(V)进行的体外实验是未知的。当在癌细胞系中测量时，PTEN的表达预测对抗HER2治疗的敏感性；此外，这种定量测量比单独使用其他途径成分更能预测疗效(相对风险3.0；95%可信区间1.6-5.5；P<；0.0001)，并在122例接受曲妥珠单抗治疗的乳腺癌队列中进行多变量分析。系统生物学方法首次成功地用于癌症个体化治疗的患者分层，并进一步令人信服地证明，在临床环境中适当地衡量PTEN，可以改善接受抗HER2治疗的患者的临床决策。[癌症资源2009；69(16)：6713-20]
Resistance to targeted cancer therapies such as trastuzumab is a frequent clinical problem not solely because of insufficient expression of HER2 receptor but also because of the overriding activation states of cell signaling pathways. Systems biology approaches lend themselves to rapid in silico testing of factors, which may confer resistance to targeted therapies. In this study, we aimed to develop a new kinetic model that could be interrogated to predict resistance to receptor tyrosine kinase (RTK) inhibitor therapies and directly test predictions in vitro and in clinical samples. The new mathematical model included RTK inhibitor antibody binding, HER2/HER3 dimerization and inhibition, AKT/mitogen-activated protein kinase cross-talk, and the regulatory properties of PTEN. The model was parameterized using quantitative phosphoprotein expression data from cancer cell lines using reverse-phase protein microarrays. Quantitative PTEN protein expression was found to be the key determinant of resistance to anti-HER2 therapy in silico, which was predictive of unseen experiments in vitro using the PTEN inhibitor bp(V). When measured in cancer cell lines, PTEN expression predicts sensitivity to anti-HER2 therapy; furthermore, this quantitative measurement is more predictive of response (relative risk, 3.0; 95% confidence interval, 1.6-5.5; P < 0.0001) than other pathway components taken in isolation and when tested by multivariate analysis in a cohort of 122 breast cancers treated with trastuzumab. For the first time, a systems biology approach has successfully been used to stratify patients for personalized therapy in cancer and is further compelling evidence that PTEN, appropriately measured in the clinical setting, refines clinical decision making in patients treated with anti-HER2 therapies. [Cancer Res 2009;69(16):6713-20]