Adapter-Layer RTK Signaling: Basic Understanding & Targeted DrugResistance

适配器层 RTK 信令：基本理解

• 批准号: 8795504
• 负责人: Aaron Samuel Meyer
• 金额: $ 36.76万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2019-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795504
• 关键词: Address; Biological; Bypass; Carcinoma; Cell Line; Cells; Clinical Trials; Decision Trees; Development; Diffusion; Disease; Drug Targeting; Effectiveness; Event; Family; Family member; Future; Homeostasis; Intention; Lead; Ligands; Link; Malignant Epithelial Cell; Malignant Neoplasms; Measurable; Measures; Mediating; Methods; Mission; Modeling; Neoplasm Metastasis; Phosphorylation; Play; Process; Proteins; Public Health; Reaction; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recruitment Activity; Regulation; Research; Resistance; Resistance Process; Role; Route; Signal Transduction; Systems Biology; Techniques; Testing; United States National Institutes of Health; Work; adapter protein; base; cancer therapy; combat; design; human MERTK protein; improved; inhibitor/antagonist; interest; neoplastic cell; predictive modeling; public health relevance; receptor; receptor binding; resistance mechanism; response; therapeutic target; therapy development; tumor

DESCRIPTION (provided by applicant): Receptor tyrosine kinases (RTKs) play a central role in regulation of cell response during development and homeostasis, and dysregulation contributes to diseases such as cancer. RTK-targeted therapies have been applied successfully in cancer treatment though with limited effectiveness as activity of non-targeted RTKs can enable cells to become resistant. While redundant signaling is now appreciated as a common mechanism of acquired and innate resistance, the exact signaling that is essential to resistance, and whether it is conserved or varies across cancer contexts, has not been addressed. RTKs lead to a common set of downstream signals, but in vastly different quantitative combinations, and differ in their ability to confer resistance in a context-dependent manner. A fundamental, rigorous understanding of resistance is necessary if we are to develop better therapies to overcome this redundancy. TAM receptors (Tyro3, AXL, MerTK) are a family of RTKs that have attracted interest for their widespread roles in tumor resistance and metastasis. However, while the ligands for these receptors have been identified, we lack even a basic understanding of the contexts that lead to activation of these receptors. RTKs work by auto- and trans-phosphorylation, recruiting adapter proteins, and then phosphorylating those adapters and other associated proteins. Systems biology has concentrated on easily measurable factors such as phosphorylation, but comparisons of signaling between receptors are not easily accomplished, as phosphosites between receptors do not readily equate. The amount of receptor-bound adapter molecules is one quantity that should be directly comparable however. Thus, I plan to develop techniques to measure RTK interaction quantitatively and across the multiple potential interactions within a cell simultaneously with the intention of more completely capturing signaling from these receptors. I will use these techniques combined with quantitative modeling to examine interactions during receptor activation and understand how different RTKs can provide redundant signaling leading to targeted cancer treatment resistance. These resistance and interaction models will then be applied to more specifically understand resistance conferred by the TAM family of RTKs. Through development of mechanistic models for ligand-dependent and independent signaling, linked to adapter interaction, downstream signaling, and tumor cell resistance, I plan to develop an integrative understanding of resistance. This will provide necessary information to develop therapies bypassing this problem.

描述（由申请人提供）：受体酪氨酸激酶（RTK）在发育和稳态期间的细胞反应调节中起着核心作用，并且失调有助于诸如癌症之类的疾病。靶向RTK的疗法已成功地用于癌症治疗中，尽管有限的有效性，因为非靶向RTK的活性可以使细胞具有抗性。虽然冗余信号现在被认为是获得和先天电阻的常见机制，但对阻力至关重要的确切信号传导尚未得到解决。 RTK会导致一组通用的下游信号，但以截然不同的定量组合形式，并且其以上下文依赖性方式赋予抵抗力的能力有所不同。如果我们要开发更好的疗法来克服这种冗余，则必须对抵抗的基本，严格的了解。 TAM受体（TYRO3，AXL，MERTK）是一个RTK家族，对其在肿瘤耐药性和转移中的广泛作用引起了人们的兴趣。但是，尽管已经确定了这些受体的配体，但我们甚至缺乏对导致这些受体激活的上下文的基本理解。 RTK通过自动和反磷酸化，募集衔接蛋白，然后磷酸化这些衔接子和其他相关蛋白的作用。系统生物学集中在易于测量的因子（例如磷酸化）上，但是受体之间的信号传导比较并不容易完成，因为受体之间的磷脂并不容易等同。但是，结合受体的适配器分子的量是应直接可比的数量。因此，我计划开发技术，以定量和跨单元内的多个潜在相互作用测量RTK相互作用，以便从这些受体中更完全捕获信号传导。我将使用这些技术与定量建模相结合来检查受体激活期间的相互作用，并了解不同的RTK如何提供冗余信号传导，从而导致靶向癌症治疗抗性。然后，这些电阻和相互作用模型将应用于RTK的TAM家族赋予的更具体地理解电阻。通过开发与配体依赖性和独立信号传导的机械模型，与衔接子相互作用，下游信号传导和肿瘤细胞耐药性相关，我计划对抗性建立综合理解。这将提供必要的信息来开发绕过此问题的疗法。