KRAS突变癌症治疗策略研究进展：从“不可成药”靶点到多元化精准治疗

Research Advances in KRAS Mutation Cancer Treatment Strategies: From “Undruggable” Targets to Diversified Precision Therapies

摘要: Kirsten大鼠肉瘤病毒癌基因同源物(Kirsten Rat Sarcoma Viral Oncogene Homolog, KRAS)基因突变是人类癌症中最常见的致癌驱动因素之一，长期因其蛋白结构平滑、与GTP结合紧密等特点被视为“不可成药”靶点。近年来，随着共价结合、变构抑制、蛋白降解等策略的突破，针对KRAS的直接抑制剂相继进入临床，标志着KRAS靶向治疗进入新时代。本文系统综述了KRAS突变癌症的治疗策略进展，涵盖直接靶向KRAS的小分子抑制剂、作用于其上游调控因子及下游信号通路的间接策略，以及新兴的蛋白降解技术、免疫疗法和基因治疗等多元化手段。同时，本文探讨了联合治疗在克服耐药性、提升疗效方面的潜力。尽管已有部分药物获批上市，KRAS靶向治疗仍面临耐药机制复杂、应答率有限等挑战。未来需进一步深化对KRAS生物学及耐药机制的理解，推动多策略联合与个体化治疗的发展。

Abstract: Mutations in the KRAS gene represent one of the most prevalent oncogenic drivers in human cancers. Historically deemed “undruggable” due to its smooth protein surface, high affinity for GTP, and lack of deep binding pockets, KRAS has long posed a major challenge for targeted therapy. In recent years, breakthrough strategies—including covalent binding, allosteric inhibition, and targeted protein degradation—have led to the development of direct KRAS inhibitors, many of which have entered clinical trials or even gained approval, heralding a new era in KRAS-targeted therapy. This review comprehensively summarizes recent advances in therapeutic strategies against KRAS-mutant cancers, covering direct small-molecule KRAS inhibitors, indirect approaches targeting upstream regulators and downstream signaling pathways, as well as emerging modalities such as proteolysis-targeting chimeras, immunotherapy and gene therapy. The potential of combination therapies to overcome resistance and enhance efficacy is also discussed. Despite the success of several agents, KRAS-targeted treatment still faces challenges such as acquired resistance and limited response rates. Future efforts should focus on elucidating KRAS biology and resistance mechanisms, and advancing combinatorial and personalized therapeutic approaches.