Identifying and Targeting Mechanisms for Membrane Signaling in Human Cancer

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.