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

描述(由申请人提供)：FOA：NOT-OD-09-058 NIH宣布恢复法案资金可用于竞争性修订申请父母赠款：5 R01 CA120247-03非小细胞肺癌(NSCLC)的腺癌亚型发病率似乎正在上升，目前约占所有肺癌病例的40%。在一组肺腺癌中发现了表皮生长因子受体(EGFR)基因的体细胞突变，这些突变与EGFR酪氨酸激酶抑制剂(TKI)erlotinib和gefitinib的敏感性有关。尽管最初的临床反应通常是戏剧性的，但几乎所有患者最终都会对这些药物产生抗药性。为了加深对肿瘤发生和对EGFR TKI耐药的了解，我们实验室通过在肺上皮细胞表达四环素诱导型突变的人EGFR转基因小鼠，建立了肺腺癌的小鼠模型。这些小鼠患上了服用多西环素的肺腺癌，停用多西环素或使用厄洛替尼治疗后，肺癌迅速消退。我们现在正在使用这个模型以及携带EGFR突变的人肺腺癌细胞株来识别可以与突变的EGFR在肿瘤发生中协同作用或对EGFR TKI产生耐药性的遗传损伤。我们将通过在体内、小鼠肺和体外细胞系中诱导睡美人(SB)转座子标记的插入突变来筛选这些基因改变。通过对在这些筛选中分离的突变的表征，我们寻求识别与人类突变的EGFR驱动的肺腺癌的发病机制或治疗反应有关的新的遗传损伤。 公共卫生相关性：我们建议扩大我们对人类肺癌小鼠模型的研究，包括使用一种名为睡美人(SB)的转座元件，这将使我们能够寻找加速EGFR启动的肿瘤发生或促进药物治疗耐药性的突变，这些问题与人类肺癌的治疗直接相关。PHS 398/2590(11/07版)页面续格式页面

DESCRIPTION (provided by applicant): FOA: NOT-OD-09-058 NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications PARENT GRANT: 5 R01 CA120247-03 The adenocarcinoma subtype of non-small cell lung cancer (NSCLC) appears to be rising in incidence and now comprises approximately 40 percent of all cases of lung cancer. Somatic mutations in the epidermal growth factor receptor (EGFR) gene have been identified in a subset of lung adenocarcinomas, and these mutations are associated with sensitivity to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Although the initial clinical response is often dramatic, virtually all patients will eventually develop resistance to these drugs. To enhance our understanding of tumorigenesis and resistance to EGFR TKIs, our laboratory has established a mouse model of lung adenocarcinoma by generating mice with tetracycline- inducible mutant human EGFR transgenes expressed in lung epithelium. These mice develop lung adenocarcinomas on doxycycline that rapidly regress in response to withdrawal of doxycycline or treatment with erlotinib. We are now using this model as well as human lung adenocarcinoma cell lines that harbor EGFR mutations to identify genetic lesions that can cooperate with mutant EGFRs in tumorigenesis or confer resistance to EGFR TKIs. We will screen for these genetic alterations by inducing Sleeping Beauty (SB) transposon-tagged insertional mutagenesis in vivo in mouse lung and in vitro in cell lines. Through characterization of the mutations isolated in these screens we seek to identify novel genetic lesions that contribute to the pathogenesis or response to treatment of human mutant EGFR-driven lung adenocarcinomas. PUBLIC HEALTH RELEVANCE: We propose to broaden our studies of mouse models of human lung cancer to include work with a transposable element, called Sleeping Beauty (SB), that will permit us to look for mutations that accelerate EGFR-initiated tumorigenesis or promote resistance to drug therapy, issues that are directly relevant to the treatment of human lung cancers. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page