Wu Ruilin, Zhu Hong, He Qiaojun, Yuan Tao, Yang Bo
Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China.
Drug Discov Today. 2024 Dec;29(12):104220. doi: 10.1016/j.drudis.2024.104220. Epub 2024 Oct 29.
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 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.
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”。尽管已经开发出了特异性的KRAS抑制剂，但其总体影响有限，这凸显了对靶向KRAS突变癌症进行进一步研究的必要性。代谢异常是癌症的关键特征，由KRAS驱动的肿瘤表现出糖酵解上调、谷氨酰胺成瘾、脂滴积累、高度活跃的巨胞饮作用以及与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提供了一种有前景的新型癌症治疗策略。本综述总结了我们对KRAS突变肿瘤细胞代谢网络理解的最新进展，讨论了潜在的可靶向弱点，并概述了相关疗法的临床进展，同时还探讨了改进针对这些侵袭性癌症策略所面临的挑战。
