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...更多
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.收起
