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

描述（由申请人提供）：肺癌是世界上最常见的癌症相关死亡原因。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这类肺癌患者策略的新知识。为了实现这些目标，我们将：(i)描述携带四环素诱导的转基因基因的基因设计小鼠的致癌特性，这些转基因基因编码在人类肺腺癌中最常见的两种突变形式的EGFR；（ii）比较在停用抗生素降低EGFR水平后发生的突变型EGFR诱导肿瘤的反应，与最近引入人类肺癌治疗的TK抑制剂（TKIs）抑制EGFR蛋白酪氨酸激酶（TK）活性后发生的肿瘤的反应；（iii）通过使用培养的人肺腺癌细胞，识别与突变EGFR维持肿瘤特性相关的信号通路成分，以及突变KRAS的假定类似特性。这将需要筛选可能干扰这些途径的化学物质和抑制性rna，然后通过在转基因动物中干扰或逆转肺肿瘤发生来验证候选信号成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.