Targeting the EGFR Pathway in Lung Adenocarcinoma

项目摘要 肺腺癌（LUAD）经常在编码表皮细胞因子的基因中发生突变。 生长因子受体（EGFR）信号通路。EGFR自身相关受体中发现突变 酪氨酸激酶（RTK）和下游信号分子。来自测序研究的新证据 我们小组和其他人对LUAD的研究也揭示了编码RTK负调控因子的基因突变 包括CBL原癌基因，一种靶向EGFR降解的E3泛素连接酶。尽管 这些遗传改变在相关和重叠的信号通路上的会聚，每个特定的 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， 肺癌各有其特点。例如，EGFR的突变是唯一的遗传性突变。 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 这些突变代表了在肺癌中使用靶向疗法的范例。然而，对 EGFR TKI不持久，肿瘤平均在药物治疗后一年内产生耐药性， 启动。对靶向EGFR的疗法的获得性耐药性是治愈或持久治疗的主要障碍。 这些患者的反应。对于其他肿瘤亚群，如CBL中携带突变的肿瘤， 迄今对这些肿瘤的生物学和药物敏感性知之甚少。在这个项目中， 通过研究LUAD中EGFR通路，我们寻求：1）阐明获得性耐药的机制， EGFR突变LUAD的治疗，2）开发合理的方法来克服EGFR导向的耐药性， 3）了解其他控制EGFR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.