Admin Supplement - Pathogenesis of Cancer - Role of EGF Receptor Endocytos

家长RO1 CA089151助学金摘要 受体酪氨酸激酶(RTK)推动多种类型癌症的发生和发展。 RTK家族的原型成员，表皮生长因子受体(EGFR)，是 在膀胱、脑、肠、结肠、卵巢、肺和头颈部过表达或突变 癌症。EGFR已成为肿瘤的主要预后指标和治疗靶点。 然而，尽管EGFR靶向治疗在一组表达 EGFR、EGFR抑制剂的结构性活性突变体对癌症无效 表达野生型EGFR。这在很大程度上可归因于机制不足。 了解体内肿瘤中涉及EGFR的致癌信号网络的调控。 我们研究的长期目标是阐明EGFR信号的调节机制 并随后有助于解决如何改善的重要临床问题 EGFR靶向治疗。我们建议通过定义以下机制来实现这一目标 哪些EGFR信号是由聚焦于过度表达的EGFR的内吞作用调节的 以颈鳞状细胞癌(HNSCC)为主要实验模型。 我们的研究旨在检验两个广泛的假设：1)EGFR内吞作用的失调是 对癌细胞的生长、存活和运动至关重要；以及2)内吞系统可以被探索到 开发新的预测/预后标记物并确定新的癌症治疗靶点。我们的 过去几年对培养细胞的研究建立了EGFR关键阶段的工作模型 体外细胞内转运。我们还开发了分析EGFR活动的方法，并 小鼠肿瘤移植瘤体内的内吞作用。我们对EGFR依赖的分析 时间分辨多重质谱法鉴定新的磷酸盐蛋白质组 内体中由EGFR启动的信号通路。我们现在处于一个独特的位置来1) EGFR依赖肿瘤细胞内EGFR转运机制的研究 模型；2)定义参与癌细胞生长和运动的主要信号通路 是由内体EGFR触发的；3)破译失调的EGFR的复杂影响 小鼠肿瘤模型中内皮细胞转运对肿瘤形成过程的影响；以及4)检验这一假说 缓慢的EGFR内吞作用与人HNSCC对治疗药物的敏感性相关 EGFR抗体，西妥昔单抗。拟议的研究将解开多方面的监管 调控异常的EGFR胞内转运对信号转导影响的机制 在体外和体内的肿瘤细胞中的过程，并开发策略使用 作为肿瘤预后标志物和治疗靶点的EGFR/RTK内吞机制。

Abstract of Parental RO1 CA089151 Grant Receptor tyrosine kinases (RTKs) drive development and progression of many types of cancer. The archetypic member of the RTK family, epidermal growth factor receptor (EGFR), is overexpressed or mutated in bladder, brain, intestinal, colon, ovarian, lung and head-and-neck cancer. EGFR has become the major prognostic marker and therapeutic target in cancer. However, despite the success of EGFR targeted therapy in a subset of cancers expressing constitutively-active mutants of EGFR, EGFR inhibitors have not been effective in cancers expressing wild-type EGFR. This is attributable in large part to insufficient mechanistic understanding of the regulation of oncogenic signaling networks involving EGFR in tumors in vivo. The long-term objective of our research is to elucidate regulatory mechanisms of EGFR signaling and subsequently contribute to addressing the important clinical question of how to improve EGFR targeted therapy. We propose to accomplish this goal by defining the mechanisms by which EGFR signaling is regulated by endocytosis focusing on EGFR overexpressing head-and- neck squamous cell carcinoma (HNSCC) as the main experimental model. Our research aims at testing two broad hypotheses: 1) dysregulation of EGFR endocytosis is critical to cancer cell growth, survival and motility; and 2) endocytic system can be explored to develop new predictive/prognostic markers and identify new cancer therapeutic targets. Our studies in cultured cells during last years established working models of key stages of EGFR endocytic trafficking in vitro. We have also developed approaches to analyze EGFR activities and endocytosis in vivo in mouse tumor xenografts. Our analysis of the EGFR-dependent phosphoproteome using time-resolved multiplexed mass-spectrometry identified new putative signaling pathways initiated by EGFR in endosomes. We are now in a unique position to 1) elucidate the mechanisms of endocytic trafficking of EGFR in vivo in EGFR-dependent tumor models; 2) define the major signaling pathways involved in growth and motility of cancer cells that are triggered by endosomal EGFR; 3) decipher the complex effects of dysregulated EGFR endocytic trafficking on tumorigenic processes in mouse tumor models; and 4) test the hypothesis that slow EGFR endocytosis correlates with the sensitivity of human HNSCC to the therapeutic EGFR antibody, cetuximab. The proposed studies will untangle the multi-faceted regulatory mechanisms underlying the impact of dysregulated EGFR endocytic trafficking on signaling processes in tumor cells in vitro and in vivo, and develop strategies for using the components of the EGFR/RTK endocytic machinery as prognostic markers and therapeutic targets in cancer.