Adapter-Layer RTK Signaling: Basic Understanding & Targeted DrugResistance

描述(由申请人提供)：受体酪氨酸激酶(RTK)在细胞发育和动态平衡期间的反应调节中发挥核心作用，调节失调导致癌症等疾病。RTK靶向治疗已经成功地应用于癌症治疗，但效果有限，因为非靶向RTK的活性可以使细胞变得具有抗药性。虽然冗余信号现在被认为是获得性和先天耐药的一种常见机制，但对耐药性至关重要的确切信号，以及它是保守的还是在癌症背景下变化的，还没有解决。RTK导致一组共同的下游信号，但在数量组合上有很大的不同，并且它们以上下文相关的方式赋予抗性的能力不同。如果我们要开发更好的治疗方法来克服这种冗余，对耐药性的基本、严格的理解是必要的。受体(Tyro3、Ax1、MerTK)是一个RTK家族，因其在肿瘤抵抗和转移中的广泛作用而引起人们的兴趣。然而，虽然这些受体的配体已经确定，但我们甚至对导致这些受体激活的背景缺乏基本的了解。RTK的工作原理是自动和反式磷酸化，招募接头蛋白，然后磷酸化这些接头和其他相关蛋白。系统生物学一直专注于容易测量的因素，如磷酸化，但受体之间的信号比较并不容易完成，因为受体之间的亚磷酸盐不容易等同。然而，与受体结合的接头分子的数量应该是直接可比较的。因此，我计划开发技术来定量地测量RTK相互作用，并同时跨越细胞内的多个潜在相互作用，目的是更全面地捕获来自这些受体的信号。我将使用这些技术结合定量建模来检查受体激活过程中的相互作用，并了解不同的RTK如何提供冗余信号导致靶向癌症治疗耐药。然后，这些阻力和相互作用模型将被用于更具体地理解家族RTK赋予的阻力。通过开发配体依赖和独立信号的机制模型，连接到接头相互作用、下游信号和肿瘤细胞耐药，我计划发展对耐药的综合理解。这将为开发绕过这一问题的治疗方法提供必要的信息。

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.