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

众所周知，携带致癌Ras突变的肿瘤对现有的靶向治疗具有抗性。 治疗这一严重的现实，加上Ras突变在一些人中普遍存在的事实， 最致命的癌症强调迫切需要确定新的靶向战略， 对于Ras驱动的肿瘤的有效疗法。这项研究计划的首要目标是 通过利用新兴的范式来满足这一需求，即Ras肿瘤的代谢重新布线 细胞构成了一个核心弱点，可以在治疗上加以利用。具体而言，我们将继续 我的实验室最近阐明了一种新颖的营养输送机制，其根源在于 我在职业生涯早期发现，致癌Ras刺激液相内吞过程 称为巨胞饮（MP）。我们最近发现这个过程被突变的Ras 细胞内化胞外蛋白并将其递送到降解产生游离氨基的地方 能为代谢途径提供燃料的酸。我们迄今为止的研究强烈表明， 这一过程的分子基础和定义其病理生理后果 为突变型Ras肿瘤定义新的干预方法的承诺。我们建议严格 通过以下三个广泛的问题来验证这个观点：1）致癌Ras如何调节MP？2)是什么 致癌Ras介导的MP？的功能后果，3）MP是否可以作为一种 治疗目标？由于我们取得的进展， 以及我们获得相关专业知识的途径。我们预计，这项研究计划将 产生新的见解Ras依赖致癌机制的翻译相关性。 .

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. .