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

抽象的。 在该奖项的前三年，我们描述了肺腺癌的小鼠模型。 由多西环素诱导的编码两种常见形式的突变EGFR的转基因启动 与之对应的人类癌症类型。这些小鼠的肿瘤与人类的肿瘤难以区分。 癌症；当癌基因被去诱导或突变激酶被抑制时，肿瘤退变 在某些情况下，它们会产生抗药性，例如 在大约一半的患者耐药肿瘤中也发现了EGFR第二次突变的结果。 我们现在建议以几种方式扩展我们在这些老鼠模型上的工作，目标是(I) 评估基因和蛋白质(包括肿瘤抑制基因、EGFR家族成员和 可能影响EGFR启动的肺肿瘤发生的蛋白)；(Ii) 发现更多与肿瘤形成、进展或耐药性有关的基因； 评估不同基因类型肿瘤转移和成为已建立细胞的可能性 以及(Iv)研究在这些小鼠中观察到的炎性细胞的来源和功能 肿瘤。为了追求这些目标，我们将利用几个有条件的小鼠突变体，结果 从我们自己的蛋白质组学调查中，睡美人转座系统和方法 免疫细胞的特征。 我们期待我们的发现为EGFR介导的肺癌发生、肿瘤的发生提供新的见解。 实体肿瘤的进展、继发性耐药和免疫细胞的作用。此外，我们 可能会产生新的小鼠肿瘤细胞系用于实验，并识别出对 肺癌的诊断、分类和治疗。

Abstract. During the first three years of this award, we have characterized mouse models of lung adenocarcinoma initiated by doxycycline-inducible transgenes encoding the two common forms of mutant EGFR found in the corresponding type of human cancer. These mice develop tumors indistinguishable from the human cancers; the tumors regress when the oncogene is de-induced or when the mutant kinase is inhibited with drugs used in patients, and they develop drug resistance under certain conditions, in some cases as a result of a secondary mutation in EGFR also found in about half of drug-resistant tumors in patients. We now propose to extend our work with these mouse models in several ways with the goals of (i) evaluating genes and proteins (including tumor suppressor genes, members of the EGFR family, and phosphotyrosine-containing proteins) that might influence EGFR-initiated lung tumorigenesis; (ii) discovering additional genes that contribute to tumor formation, progression or drug resistance; (iii) assessing the potential of tumors with various genotypes to metastasize and become established cell lines in culture; and (iv) studying the origins and functions of inflammatory cells observed in these mouse tumors. To pursue these goals, we will take advantage of several conditional mouse mutants, results from our own proteomics surveys, the Sleeping Beauty transposition system, and methods for characterization of immune cells. We expect our findings to offer new insights into EGFR-mediated lung carcinogenesis, tumor progression, secondary drug resistance, and the role of immune cells in solid tumors. In addition, we may generate new mouse tumor cell lines for experimental use and identify genes that are useful for diagnosis, classification, and treatment of lung cancers.