文章：

KRAS突变在结直肠癌中的作用：生物学见解、临床意义及未来治疗前景

The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives

原文发布日期：27 January 2025

DOI: 10.3390/cancers17030428

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with KRAS mutations occurring in 30–40% of cases, contributing to poor prognosis and resistance to anti-EGFR therapy. This review explores the biological significance, clinical implications, and therapeutic targeting of KRAS mutations in CRC.Methods: A comprehensive analysis of the existing literature and clinical trials was performed, highlighting the role of KRAS mutations in CRC pathogenesis, their impact on prognosis, and recent advancements in targeted therapies. Specific attention was given to emerging therapeutic strategies and resistance mechanisms.Results: KRAS mutations drive tumor progression through persistent activation of MAPK/ERK and PI3K/AKT signaling pathways. These mutations influence the tumor microenvironment, cancer stem cell formation, macropinocytosis, and cell competition. KRAS-mutant CRC exhibits poor responsiveness to anti-EGFR monoclonal antibodies and demonstrates primary and acquired resistance to KRAS inhibitors. Recent breakthroughs include the development of KRAS G12C inhibitors (sotorasib and adagrasib) and promising agents targeting G12D mutations. However, response rates in CRC remain suboptimal compared to other cancers, necessitating combination therapies and novel approaches, such as vaccines, nucleic acid-based therapeutics, and macropinocytosis inhibitors.Conclusions: KRAS mutations are central to CRC pathogenesis and present a significant therapeutic challenge. Advances in KRAS-targeted therapies offer hope for improved outcomes, but resistance mechanisms and organ-specific differences limit efficacy. Continued efforts in personalized treatment strategies and translational research are critical for overcoming these challenges and improving patient survival.

摘要翻译： 

**背景/目的：** 结直肠癌（CRC）仍是全球癌症死亡的主要原因之一，其中30-40%的病例存在KRAS突变，导致预后不良及对抗EGFR治疗耐药。本综述探讨了KRAS突变在CRC中的生物学意义、临床影响及治疗靶向性。 **方法：** 对现有文献及临床试验进行全面分析，重点阐述KRAS突变在CRC发病机制中的作用、其对预后的影响以及靶向治疗的最新进展。特别关注新兴治疗策略及耐药机制。 **结果：** KRAS突变通过持续激活MAPK/ERK和PI3K/AKT信号通路驱动肿瘤进展。这些突变影响肿瘤微环境、癌症干细胞形成、巨胞饮作用及细胞竞争。KRAS突变型CRC对抗EGFR单克隆抗体反应性差，并对KRAS抑制剂表现出原发性和获得性耐药。近期突破包括KRAS G12C抑制剂（sotorasib和adagrasib）的研发以及针对G12D突变的有前景药物。然而，与其他癌症相比，CRC中的应答率仍不理想，需要联合疗法及新方法，如疫苗、核酸疗法和巨胞饮抑制剂。 **结论：** KRAS突变是CRC发病机制的核心，并构成重大治疗挑战。KRAS靶向治疗的进展为改善预后带来希望，但耐药机制及器官特异性差异限制了疗效。持续推动个体化治疗策略和转化研究对于克服这些挑战、提高患者生存率至关重要。

原文链接：

The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives