Targeting EGFR and KRAS Mutations

三线研究表明，EGFR或KRAS突变的肺腺癌 原癌基因依赖于癌基因的持续功能：（1）人类肿瘤在 对EGFR抑制剂的反应，（2）当突变体 癌基因被药物下调或抑制，和（3）来自人肺的细胞系 腺癌对等位基因特异性抑制性RNA和EGFR抑制剂敏感。这些发现 表明有可能开发出更有效的方法来治疗肺腺癌， 了解更多关于突变EGFR或KRAS驱动的信号通路的基本组成部分。到 为了实现这一可能性，我们将使用充分表征的人类细胞系，转基因小鼠，化学文库， 和新的蛋白质化学方法来鉴定这些成分。具体来说，我们将使用高 通量，针对小分子文库对肺腺癌细胞系进行基于细胞的筛选，以鉴定 一些化合物的分子靶标具有强烈的生长抑制或细胞死亡诱导活性。 此外，我们还将鉴定人类细胞中与突变EGFR相关或被突变EGFR磷酸化的蛋白质， 系或转基因小鼠肿瘤。选定的蛋白质将进一步研究，通过操纵和分析 它们在细胞系和转基因小鼠中的表达。

Three lines of investigation demonstrate that lung adenocarcinomaswith mutations in the EGFR or KRAS proto-oncogenes are dependent on continued function of the oncogenes: (1) human tumors regress in response to EGFR inhibitors, (2) lung adenocarcinomasin mouse models disappear when mutant oncogenes are down-regulated or inhibited by drugs, and (3) cell lines derived from human lung adenocarcinomas are sensitive to allele-specific inhibitory RNAs and EGFR inhibitors. These findings suggest that it may be possible to develop more effective means to treat adenocarcinoma of the lung by; learning more about essential components of signaling pathwaysdriven by mutant EGFR or KRAS. To approach this possibility, we will use well-characterized human cell lines, transgenic mice, chemical libraries, and new protein chemistry methods to identify such components. Specifically, we will use a high throughput, cell-based screen of lung adenocarcinoma cell lines against small molecule libraries to identify the molecular targets of a few compounds that have strong growth-inhibitory or cell death-inducing activity. In addition, we will identify proteins that are affiliated with or phosphorylated by mutant EGFRs in human cell lines or transgenic mouse tumors. Selected proteins will be studied further by manipulating and analyzing their expression in cell lines and transgenic mice.