Oncogenic Ras-induced macropinocytosis: A new paradigm for metabolic adaptation

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Tumors harboring oncogenic Ras mutations are notoriously resistant to existing targeted therapies. This grave reality coupled with the fact that Ras mutations are prevalent in some of the deadliest cancers underscore the urgent need to identify new targeting strategies that can be translated to effective therapies for Ras-driven tumors. The overarching goal of this research program is to address this need by capitalizing on the emerging paradigm that the metabolic rewiring of Ras tumor cells constitutes a core vulnerability that can be exploited therapeutically. Specifically, we will pursue a novel nutrient delivery mechanism that was recently elucidated in my laboratory and is rooted in a discovery I made earlier in my career that oncogenic Ras stimulates a fluid-phase endocytic process known as macropinocytosis (MP). We recently discovered that this process is exploited by mutant Ras cells to internalize extracellular protein and deliver it to where it is degraded to generate free amino acids that can fuel metabolic pathways. Our studies to date strongly indicate that understanding the molecular underpinnings of this process and defining its pathophysiological consequences hold promise for defining new intervention approaches for mutant Ras tumors. We propose to rigorously test this idea by pursuing three broad questions: 1) How does oncogenic Ras regulate MP? 2) What are the functional consequences of oncogenic-Ras mediated MP?, and 3) Can MP be exploited as a therapeutic target? We are uniquely positioned to address these questions owing to the progress we have made thus far and our access to relevant expertise. We anticipate that this research program will yield new insights into Ras-dependent oncogenic mechanisms of translational relevance. .