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

描述(申请人提供)：肺癌是世界上最常见的癌症相关死亡原因。最近的发现表明，肺癌可以根据特定原癌基因的突变进行细分。人类肺腺癌的一个亚群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。这项提议的总体目标是使用来自人类肺癌的基因工程小鼠和细胞系来扩大我们对这一肺腺癌亚型的了解，并获得可能改进治疗这种类型肺癌患者的策略的新知识。为了追求这些目标，我们将：(I)鉴定携带四环素诱导的转基因小鼠的致癌特性，这些转基因编码在人类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诱导的肿瘤与通过给予最近引入的TK抑制剂(TKIs)抑制EGFR蛋白酪氨酸激酶(TK)活性后发生的突变EGFR诱导的肿瘤的反应；以及(Iii)通过使用人肺腺癌的培养细胞，鉴定参与突变的EGFR的肿瘤维持特性和突变的KRAS的假定相似特性的信号通路的组件。这将需要筛选可能干扰这些途径的化学物质和抑制RNA，然后通过干扰或逆转转基因动物的肺肿瘤发生来验证候选信号成分和抑制化学物质。

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.