Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Adv Cancer Res. 2022;153:267-304. doi: 10.1016/bs.acr.2021.07.010. Epub 2021 Aug 26.
RAS mutations are among the most frequent oncogenic drivers observed in human cancers. With a lack of available treatment options, RAS-mutant cancers account for many of the deadliest cancers in the United States. Recent studies established that altered metabolic requirements are a hallmark of cancer, and many of these alterations are driven by aberrant RAS signaling. Specifically, RAS-driven cancers are characterized by upregulated glycolysis, the differential channeling of glycolytic intermediates, upregulated nutrient scavenging pathways such as autophagy and macropinocytosis, and altered glutamine utilization and mitochondrial function. This unique metabolic landscape promotes tumorigenesis, proliferation, survival in nutrient deficient environments and confers resistance to conventional cytotoxic and targeted therapies. Emerging work demonstrates how these dependencies can be therapeutically exploited in vitro and in vivo with many metabolic inhibitors currently in clinical trials. This review aims to outline the unique metabolic requirements induced by aberrant RAS signaling and how these altered dependencies present opportunities for therapeutic intervention.
RAS 突变是人类癌症中最常见的致癌驱动因素之一。由于缺乏有效的治疗选择，RAS 突变型癌症占美国许多最致命癌症的比例。最近的研究表明，改变的代谢需求是癌症的一个标志，其中许多改变是由异常的 RAS 信号驱动的。具体来说，RAS 驱动的癌症的特征是糖酵解上调、糖酵解中间产物的差异通道化、自噬和巨胞饮等上调的营养物质摄取途径、以及改变的谷氨酰胺利用和线粒体功能。这种独特的代谢景观促进了肿瘤发生、增殖、在营养缺乏的环境中存活，并赋予了对传统细胞毒性和靶向治疗的耐药性。新兴的研究工作表明，这些依赖性如何可以在体外和体内利用许多目前正在临床试验中的代谢抑制剂进行治疗性利用。这篇综述旨在概述异常 RAS 信号诱导的独特代谢需求，以及这些改变的依赖性如何为治疗干预提供机会。
