Mutant EGF Receptor-Dependent Lung Cancer in Human Cell Lines and Transgenic Mice

描述（由申请人提供）：肺癌是世界上癌症相关死亡的最常见原因。最近的研究结果表明，肺癌可以根据特定原癌基因的突变进行细分。人肺腺癌的一个子集依赖于突变的表皮生长因子受体（EGFR）基因，并对抑制蛋白酪氨酸激酶的药物有反应。本提案的总体目标是使用基因工程小鼠和源自人类肺癌的细胞系来扩大我们对肺腺癌这一亚群的理解，并获得可能改善治疗此类肺癌患者的策略的新知识。在追求这些目标的过程中，我们将：（i）表征携带四环素诱导转基因的基因设计小鼠的致癌特性，所述转基因编码在人肺腺癌中最常见的两种EGFR突变形式;（ii）比较通过停用抗生素降低EGFR水平后发生的突变EGFR诱导的肿瘤的反应与抑制EGFR蛋白酪氨酸激酶（TK）后发生的反应，活性的TK抑制剂（TKI）最近引入到人类肺癌的治疗管理;和（iii）通过使用培养的细胞从人肺腺癌的突变型EGFR和突变型KRAS的假定类似性质的肿瘤维持参与的信号通路的组件。这将需要筛选可能干扰这些途径的化学物质和抑制性RNA，然后通过干扰或逆转转基因动物中的肺肿瘤发生来验证候选信号传导组分和抑制性化学物质。

DESCRIPTION (provided by applicant): Lung cancer is the most common cause of cancer-related mortality in the world. Recent findings suggest that lung cancers can be subdivided according to mutations in specific proto-oncogenes. One subset of human lung adenocarcinomas is dependent on mutant epidermal growth factor receptor (EGFR) genes and responsive to drugs that inhibit protein-tyrosine kinases. The overall goals of this proposal are to use genetically engineered mice and cell lines derived from human lung cancers to enlarge our understanding of this subset of lung adenocarcinomas and to acquire new knowledge that might improve strategies for treating patients with this type of lung cancer. In pursuit of these goals, we will: (i) characterize the oncogenic properties of genetically designed mice carrying tetracycline-inducible transgenes that encode the two mutant forms of EGFR observed most commonly in human lung adenocarcinomas; (ii) compare the responses of mutant EGFR-induced tumors that occur after reduction of EGFR levels by withdrawal of antibiotics with those that occur after inhibition of EGFR protein-tyrosine kinase (TK) activity by administration of TK inhibitors (TKIs) recently introduced into therapy of human lung cancer; and (iii) identify components of the signaling pathways involved in the tumor-maintaining properties of mutant EGFR and the presumptive analogous properties of mutant KRAS by using cultured cells from human lung adenocarcinomas. This will entail screening for chemicals and inhibitory RNAs that may interfere with those pathways followed by validation of candidate signaling components and inhibitory chemicals by either interfering with or reversing lung tumorigenesis in transgenic animals.