EGFR PATHWAY ALTERATIONS IN LUNG TUMORS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 表皮生长因子受体（EGFR）过度表达在肺肿瘤和癌前病变中经常被观察到，并在动物研究中诱导肿瘤形成。EGFR调节癌发生中的重要过程，包括细胞存活、细胞周期进展、肿瘤侵袭和血管生成。 在最近FDA批准的非小细胞肺癌（NSCLC）治疗中，已在临床上观察到阻断EGFR活化的EGFR酪氨酸激酶抑制剂（EGFR-TKI）的疗效。 然而，患者对这些药物的反应性差异很大，可靠的预测因子尚未确定或验证。尽管这一途径具有临床重要性，但导致EGFR改变的特定因素在很大程度上仍不清楚，有证据表明它们在非吸烟者中更常见。 - 假设-作为关注的致癌金属，我们假设砷和镍暴露改变EGFR信号传导和/或促进EGFR基因突变。 - 方法-我们建议在两个实验系统中研究砷和镍在EGFR通路调节中的作用：1）在使用BEAS-2B人肺上皮细胞系的细胞培养中，和2）在从早期非小细胞肺癌病例（在COBRE项目5中登记）获得的肿瘤标本中。 - 相关性-这些研究将为促进肺癌发生的特定环境因子提供新的机制见解。 表征影响EGFR信号通路的暴露将有助于优化靶向筛查和分子诊断的使用。 然后，我们可以确定潜在的反应病例的子集，谁将受益于药理学EGFR抑制作为肺部治疗策略。

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.