Metabolic reprogramming in KRAS-mutant cancers: Proven targetable vulnerabilities and potential therapeutic strategies

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today Pub Date : 2024-10-29 DOI:10.1016/j.drudis.2024.104220

Ruilin Wu , Hong Zhu , Qiaojun He , Tao Yuan , Bo Yang

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引用次数: 0

Abstract

Kras (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), one of the most frequently mutated oncogenes in the human genome, is considered ‘untargetable’. Although specific KRAS^G12C inhibitors have been developed, their overall impact is limited, highlighting the need for further research on targeting KRAS-mutant cancers. Metabolic abnormalities are key hallmarks of cancer, with KRAS-driven tumors exhibiting traits like glycolysis upregulation, glutamine addiction, lipid droplet accumulation, highly active macropinocytosis, and metabolic reprogramming-associated tumor microenvironment remodeling. Targeting these unique metabolic characteristics offers a promising strategy for new cancer treatments. This review summarizes recent advances in our understanding of the metabolic network in KRAS-mutated tumor cells, discusses potential targetable vulnerabilities, and outlines clinical developments in relevant therapies, while also addressing challenges to improve strategies against these aggressive cancers.

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KRAS突变癌症的代谢重编程：已证实的靶向弱点和潜在的治疗策略。

Kras（Ki-ras2 Kirsten大鼠肉瘤病毒癌基因同源物）是人类基因组中最常发生突变的癌基因之一，被认为是 "不可靶向 "的。虽然已经开发出了特异性 KRASG12C 抑制剂，但其总体影响有限，这凸显了针对 KRAS 突变癌症开展进一步研究的必要性。代谢异常是癌症的关键特征，KRAS 驱动的肿瘤表现出糖酵解上调、谷氨酰胺成瘾、脂滴积累、高活性大细胞增多以及代谢重编程相关的肿瘤微环境重塑等特征。针对这些独特的代谢特征，为新的癌症治疗提供了一种前景广阔的策略。这篇综述总结了我们对 KRAS 突变肿瘤细胞代谢网络的最新理解进展，讨论了潜在的靶向弱点，概述了相关疗法的临床发展，同时也探讨了改进这些侵袭性癌症治疗策略所面临的挑战。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Discovery Today 医学-药学

CiteScore

14.80

自引率

2.70%

发文量

293

审稿时长

6 months

期刊介绍： Drug Discovery Today delivers informed and highly current reviews for the discovery community. The magazine addresses not only the rapid scientific developments in drug discovery associated technologies but also the management, commercial and regulatory issues that increasingly play a part in how R&D is planned, structured and executed. Features include comment by international experts, news and analysis of important developments, reviews of key scientific and strategic issues, overviews of recent progress in specific therapeutic areas and conference reports.