Identifying and Targeting Mechanisms for Membrane Signaling in Human Cancer

项目总结 肺癌是全球癌症死亡的主要原因。最常见的肺癌类型是非 小细胞肺癌(NSCLC)。在NSCLC中，最常见的亚型是腺癌(LUAD)。这个 此应用程序的目标是实施涉及两个PI的协作工作，这些PI具有互补的专业知识 临床前模型、蛋白质组学和功能基因组学了解RhoA和RAP1GDS1在 在LUAD推动致癌KRAS我们广泛的初步数据表明，封锁联合损失 RhoA和RAP1GDS1导致KRAS依赖的细胞增殖减少和细胞凋亡增加 举止。斯威特-科德罗实验室和杰克逊实验室在过去的几年里进行了密集的合作 数年来，我们首先要找出这种人为的脆弱性，其次要了解其背后的机制基础。 在目标1中，我们将使用功能和细胞生物学方法来定义RAP1GDS1在细胞中的作用 3D模式下的扩散和增长。我们还将扩大我们的研究范围，以评估其他Rho蛋白在 与RAP1GDS1的相互作用。在目标2中，我们将使用蛋白质组学方法进一步阐明 RAP1GDS1缺失的后果，特别是RAP1GDS1长亚型和短亚型之间的差异 蛋白质参与细胞信号的调节。最后，在目标3中，我们提出了一系列涉及两者的实验 LUAD的PDX模型和LUAD的GEM模型，以进一步阐明相互作用的基因型特异性 RAP1GDS1和RhoA之间。我们还将探索这一组合的潜在治疗意义。 使用Rock抑制剂的脆弱性和抑制RAP1GDS1与关键下游蛋白的相互作用。

PROJECT SUMMARY Lung cancer is the leading cause of cancer deaths worldwide. The most prevalent type of lung cancer is Non- Small Cell Lung Cancer (NSCLC). Within NSCLC, the most common subtype is adenocarcinoma (LUAD). The goal of this application is to implement a collaborative effort involving two PIs with complimentary expertise in preclinical models, proteomics and functional genomics to understand the role of RhoA and RAP1GDS1 in driving oncogenic KRAS in LUAD Our extensive preliminary data indicates that blockade of combined loss of RhoA and RAP1GDS1 leads to decreased proliferation and increased apoptosis in a KRAS-dependent manner. The Sweet-Cordero and Jackson laboratories have collaborated intensively over the past several years first to identify this synthetic vulnerability and second to understand the mechanistic basis underlying it. In Aim 1, we will use functional and cell biology approaches to define the role of RAP1GDS1 in cell proliferation and growth in 3D. We will also expand our studies to evaluate the role of other Rho proteins as interactors with RAP1GDS1. In Aim 2, we will use proteomic approaches to further elucidate the consequences of RAP1GDS1 loss and specifically the differences between the long and short isoforms of this protein in the regulation of cell signaling. Finally, in Aim 3, we propose a series of experiments involving both PDX models of LUAD and GEM models of LUAD to further elucidate the genotype specificity of the interaction between RAP1GDS1 and RhoA. We will also explore the potential therapeutic implications of this combined vulnerability using Rock inhibitors and inhibition of RAP1GDS1 interaction with key downstream proteins.