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美国国立卫生研究院宣布为竞争性修订申请提供恢复法案基金父母资助：5 R01 CA120247-03非小细胞肺癌（NSCLC）的腺癌亚型的发病率似乎正在上升，目前约占肺癌所有病例的40%。表皮生长因子受体（EGFR）基因的体细胞突变已经在肺腺癌的一个亚群中被发现，这些突变与对EGFR酪氨酸激酶抑制剂（TKIs）厄洛替尼和吉非替尼的敏感性有关。虽然最初的临床反应往往是戏剧性的，但几乎所有患者最终都会对这些药物产生耐药性。为了加强我们对肿瘤发生和对EGFR TKIs的耐药性的了解，我们实验室通过在肺上皮中表达四环素诱导的突变型人EGFR转基因小鼠建立了肺腺癌小鼠模型。这些小鼠在服用强力霉素后发生肺腺癌，在停用强力霉素或厄洛替尼治疗后迅速消退。我们现在正在使用该模型以及含有EGFR突变的人肺腺癌细胞系来识别在肿瘤发生过程中可以与突变的EGFR合作或赋予对EGFR TKIs的抗性的遗传病变。我们将通过诱导睡美人（SB）转座子标记的插入突变，在小鼠肺和体外细胞系中筛选这些遗传改变。通过对这些筛选中分离的突变的表征，我们试图确定有助于人类突变egfr驱动的肺腺癌的发病机制或治疗反应的新的遗传病变。

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