He Dongsheng, Bai Rilan, Chen Naifei, Cui Jiuwei
Cancer Center, the First Hospital of Jilin University, Changchun 130021, China.
Chin J Cancer Res. 2024 Aug 30;36(4):421-441. doi: 10.21147/j.issn.1000-9604.2024.04.06.
Kirsten rat sarcoma viral oncogene homolog () is the most frequently mutated oncogene, occurring in various tumor types. Despite extensive efforts over the past 40 years to develop inhibitors targeting KRAS mutations, resistance to these inhibitors has eventually emerged. A more precise understanding of KRAS mutations and the mechanism of resistance development is essential for creating novel inhibitors that target specifically KRAS mutations and can delay or overcome resistance. Immunotherapy has developed rapidly in recent years, and in-depth dissection of the tumor immune microenvironment has led researchers to shift their focus to patients with KRAS mutations, finding that immune factors play an essential role in KRAS-mutant (KRAS-Mut) tumor therapy and targeted drug resistance. Breakthroughs and transitions from targeted therapy to immunotherapy have provided new hope for treating refractory patients. Here, we reviewed KRAS mutation-targeted treatment strategies and resistance issues, focusing on our in-depth exploration of the specific immune status of patients with KRAS mutations and the impact of body immunity following KRAS inhibition. We aimed to guide innovative approaches combining RAS inhibition with immunotherapy, review advances in preclinical and clinical stages, and discuss challenges and future directions.
Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS）是最常发生突变的癌基因，存在于多种肿瘤类型中。尽管在过去40年里人们付出了巨大努力来开发针对KRAS突变的抑制剂，但最终还是出现了对这些抑制剂的耐药性。更精确地了解KRAS突变及耐药性产生的机制，对于开发能够特异性靶向KRAS突变并可延缓或克服耐药性的新型抑制剂至关重要。近年来免疫疗法发展迅速，对肿瘤免疫微环境的深入剖析使研究人员将目光转向KRAS突变患者，发现免疫因素在KRAS突变（KRAS-Mut）肿瘤治疗及靶向药物耐药中起着至关重要的作用。从靶向治疗到免疫治疗的突破与转变为难治性患者的治疗带来了新希望。在此，我们综述了KRAS突变靶向治疗策略及耐药问题，重点深入探讨了KRAS突变患者的特异性免疫状态以及KRAS抑制后机体免疫的影响。我们旨在指导将RAS抑制与免疫疗法相结合的创新方法，回顾临床前和临床阶段的进展，并讨论挑战和未来方向。
