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

携带致癌RAS突变的肿瘤对现有的靶向耐药是出了名的 治疗。这一严峻的现实加上RAS突变在一些 最致命的癌症强调了确定可翻译的新靶向策略的迫切需要 到RAS驱动的肿瘤的有效治疗。这项研究计划的首要目标是 通过利用RAS肿瘤的代谢重连这一新兴范式来满足这一需求 细胞构成了可用于治疗的核心脆弱性。具体地说，我们将推行 我的实验室最近阐明了一种新的营养输送机制，它植根于 我在职业生涯早期发现致癌RAS刺激液体相内吞过程 称为巨噬细胞增多症(MP)。我们最近发现，突变的RAS利用了这一过程 细胞内化胞外蛋白并将其输送到被降解的地方以产生游离氨基 可以为新陈代谢途径提供燃料的酸。我们到目前为止的研究强烈表明，理解 这一过程的分子基础及其病理生理后果的定义成立 承诺为突变的RAS肿瘤定义新的干预方法。我们严正建议 通过三个广泛的问题来检验这个想法：1)致癌的RAS如何调节MP？2)什么是 致癌-RAS介导的MP的功能后果？3)MP可以作为一种 治疗目标？由于我们取得的进展，我们在解决这些问题方面处于独特的地位 到目前为止已经取得的进展以及我们获得相关专业知识的机会。我们预计这项研究计划将 对RAS依赖的翻译相关性致癌机制产生新的见解。 。

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. .