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

家长RO 1 CA 089151补助金摘要 受体酪氨酸激酶（RTK）驱动许多类型癌症的发展和进展。 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、肺和头颈部过度表达或突变 癌EGFR已成为肿瘤的主要预后标志物和治疗靶点。 然而，尽管EGFR靶向治疗在表达EGFR的癌症亚组中取得了成功， EGFR的组成型活性突变体，EGFR抑制剂在癌症中无效 表达野生型EGFR。这在很大程度上是由于机械性不足。 了解体内肿瘤中涉及EGFR的致癌信号网络的调节。 本研究的长期目标是阐明EGFR信号转导的调控机制 并随后有助于解决如何改善的重要临床问题 EGFR靶向治疗。我们建议通过以下方式确定机制来实现这一目标： 其中EGFR信号传导受内吞作用调节，所述内吞作用集中于EGFR过表达的头部和- 颈部鳞状细胞癌（HNSCC）为主要实验模型。 我们的研究旨在验证两个广泛的假设：1）EGFR内吞失调是 对癌细胞生长、存活和运动至关重要;和2）可以探索内吞系统， 开发新的预测/预后标志物，并确定新的癌症治疗靶点。我们 近年来在培养细胞中的研究建立了EGFR关键阶段的工作模型， 体外内吞运输。我们还开发了分析EGFR活性的方法， 在小鼠肿瘤异种移植物中的体内内吞作用。我们对EGFR依赖性的 磷酸化蛋白质组使用时间分辨多重质谱鉴定新的推定 EGFR在核内体中启动的信号通路。我们现在处于一个独特的位置，1） 阐明EGFR依赖性肿瘤中EGFR的体内内吞转运机制 模型; 2）定义参与癌细胞生长和运动的主要信号传导途径， 由内体EGFR触发; 3）解读EGFR失调的复杂效应 内吞运输对小鼠肿瘤模型中的肿瘤发生过程的影响;以及4）检验假设 减缓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 EGFR内吞转运失调对信号传导影响的潜在机制 过程中的肿瘤细胞在体外和体内，并制定战略，使用的组成部分， EGFR/RTK内吞机制作为癌症的预后标志物和治疗靶点。

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.