EGFR PATHWAY ALTERATIONS IN LUNG TUMORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景-在动物研究中，表皮生长因子受体(EGFR)的过度表达经常在肺癌和癌前病变中观察到，并诱导肿瘤的形成。EGFR调节肿瘤发生中的重要过程，包括细胞存活、细胞周期进展、肿瘤侵袭和血管生成。在FDA最近批准的非小细胞肺癌(NSCLC)治疗中，已经在临床上观察了EGFR酪氨酸激酶抑制剂(EGFR-TKI)阻断EGFR激活的疗效。然而，不同患者对这些药物的反应差异很大，可靠的预测因素尚未确定或验证。尽管这一途径具有临床重要性，但导致EGFR改变的具体因素仍然很大程度上尚不清楚，而且有证据表明，它们更常发生在非吸烟者中。 -假设-作为令人关注的致癌金属，我们假设砷和镍暴露改变了EGFR信号和/或促进了EGFR基因的突变。 -方法-我们建议在两个实验系统中研究砷和镍在EGFR途径调控中的作用：1)使用BEAS-2B人肺上皮细胞系进行细胞培养，以及2)从早期非小细胞肺癌病例(参加Cobre项目5)获得的肿瘤标本。 -相关性--这些研究将为促进肺癌发生的特定环境因素提供新的机械性见解。确定影响EGFR信号通路的暴露的特征将有助于优化靶向筛查和分子诊断的使用。然后，我们可以确定潜在反应性病例的亚组，以及谁将受益于作为肺部治疗策略的药物EGFR抑制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background - Epidermal growth factor receptor (EGFR) over-expression is frequently observed in lung tumors and pre-cancerous lesion and induces tumor formation in animal studies. EGFR regulates important processes in carcinogenesis, including cell survival, cell-cycle progression, tumor invasion, and angiogenesis. Therapeutic efficacy with EGFR tyrosine kinase inhibitors (EGFR-TKI) that block EGFR activation is already being observed clinically in the recently FDA-approved treatment of non-small cell lung cancer (NSCLC). Yet, responsiveness to these drugs varies dramatically between patients, and reliable predictors have not been identified or validated. Despite the clinical importance of this pathway, those specific factors that cause alterations in EGFR remain largely unknown and there is evidence that they occur more frequently in non-smokers. -Hypothesis - As carcinogenic metals of concern, we hypothesize that arsenic and nickel exposure alter EGFR signaling and or promote mutations in the EGFR gene. -Approach - We propose to investigate the role of arsenic and nickel in EGFR pathway regulation in two experimental systems: 1) in cell culture using the BEAS-2B human lung epithelial cell lines, and 2) in tumor specimens obtained from early stage non-small cell lung cancer cases (enrolled in COBRE project 5). -Relevance - These studies will provide new mechanistic insights into specific environmental agents that promote lung carcinogenesis. Characterizing an exposure that impacts the EGFR signaling pathway will help optimize use of targeted screening and molecular diagnostics. We can then identify subsets of potentially responsive cases and who will benefit from pharmacologic EGFR inhibition as a therapeutic strategy in the lung.