Targeting the EGFR Pathway in Lung Adenocarcinoma

项目总结 肺腺癌(LUAD)通常含有编码表皮成分的基因突变。 生长因子受体(EGFR)信号通路。在EGFR本身中发现突变，相关受体 酪氨酸激酶(RTK)和下游信号分子。来自测序研究的新证据 我们和其他人对LUAD的研究也发现了RTK负调控因子编码基因的突变 包括CBL原癌基因，一种针对EGFR降解的E3泛素连接酶。尽管 这些基因改变在相关和重叠的信号通路上的收敛，每个信号通路都是特定的 突变决定了疾病对不同疗法的敏感性，并定义了独特的临床亚群 肺癌每一种都有自己的一套特征。例如，EGFR的突变是唯一的基因 与酪氨酸激酶抑制剂(TKI)吉非替尼和厄洛替尼敏感性相关的改变。肿瘤与 这些突变代表了在肺癌中使用靶向治疗的范例。然而，对此的回应 EGFR TKI无法持续，肿瘤平均在药物治疗后一年内变得耐药 已启动。对针对EGFR的治疗的获得性抵抗是治疗或持久的主要障碍 对这些患者的反应。对于其他亚型的肿瘤，例如那些含有CBL突变的肿瘤，非常 到目前为止，人们对这些肿瘤的生物学和药物敏感性知之甚少。在本项目中，以 在LUAD中的EGFR途径，我们试图1)阐明获得性耐药的机制 EGFR突变型LUAD的治疗，2)开发合理的方法来克服对EGFR导向的耐药性 治疗和，3)了解具有控制EGFR的其他基因突变的LUAD的脆弱性 发信号。

PROJECT SUMMARY Lung adenocarcinomas (LUADs) frequently harbor mutations in genes encoding components of the Epidermal Growth Factor Receptor (EGFR) signaling pathway. Mutations are found in EGFR itself, related receptor tyrosine kinases (RTKs) and in downstream signaling molecules. Emerging evidence from sequencing studies of LUADs by our group and others has also revealed mutations in genes encoding negative regulators of RTKs including the CBL proto-oncogene, an E3 ubiquitin ligase that targets EGFR for degradation. Despite the convergence of these genetic alterations on related and overlapping signaling pathways, each specific mutation determines the sensitivity of the disease to different therapies and defines unique clinical subsets of lung cancer each with its own set of characteristics. For example, mutations in EGFR are the only genetic alteration associated with sensitivity to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Tumors with these mutations represent a paradigm for the use of targeted therapies in lung cancer. However, responses to EGFR TKIs are not sustained and tumors become resistant on average within a year after drug-treatment is initiated. Acquired resistance to therapies targeting the EGFR is a major impediment to cures or durable responses for these patients. For other subsets of tumors, such as those harboring mutations in CBL, very little is known to date on the biology and drug sensitivity of these tumors. In this project, centered on the EGFR pathway in LUADs, we seek 1) to clarify the mechanisms of acquired resistance to EGFR-directed therapies in EGFR mutant LUADs, 2) to develop rational approaches to overcome resistance to EGFR-directed therapies and, 3) to understand the vulnerabilities of LUADs with mutations in other genes that control EGFR signaling.