Colorectal cancer (CRC) is one of the most common cancers worldwide, with KRAS mutations occurring in approximately 40% of cases. These mutations drive tumorigenesis through the constitutive activation of key signaling pathways, such as RAS-RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR, contributing to therapeutic resistance and poor prognosis. Advances in molecular biology have led to significant breakthroughs, including the development of KRAS G12C inhibitors, such as sotorasib and adagrasib, which have shown promise in clinical trials. However, their efficacy is limited to a small subset of KRAS-mutant CRC, and resistance mechanisms often emerge through compensatory pathway activation. Combination strategies, including KRAS inhibitors with anti-EGFR agents, have been explored in trials like KRYSTAL-1 and CodeBreaK 300. Emerging research highlights the role of the tumor microenvironment in immune evasion and therapeutic resistance, offering opportunities for novel immunotherapy approaches, including KRAS neoantigen vaccines and adoptive T-cell therapy. Despite these advancements, challenges such as intratumoral heterogeneity, limited immune infiltration, and non-G12C KRAS mutations remain significant hurdles. This review provides a comprehensive overview of the molecular mechanisms, current advances and challenges, and future prospects in the management of KRAS-mutant CRC.
结直肠癌是全球最常见的恶性肿瘤之一，其中约40%的病例存在KRAS基因突变。这类突变通过持续激活RAS-RAF-MEK-ERK（MAPK）和PI3K-AKT-mTOR等关键信号通路驱动肿瘤发生，导致治疗耐药及预后不良。分子生物学进展已带来重要突破，包括KRAS G12C抑制剂（如sotorasib与adagrasib）的研发，这些药物在临床试验中展现出治疗潜力。然而，其疗效目前仅限于KRAS突变结直肠癌中的小部分亚型，且常因代偿性通路激活而产生耐药机制。联合治疗策略（如KRAS抑制剂联合抗EGFR药物）已在KRYSTAL-1和CodeBreaK 300等试验中开展探索。新兴研究揭示了肿瘤微环境在免疫逃逸和治疗耐药中的作用，为KRAS新抗原疫苗、过继性T细胞疗法等新型免疫治疗方案提供了发展机遇。尽管取得这些进展，肿瘤内异质性、免疫浸润受限及非G12C型KRAS突变等问题仍是当前面临的重要挑战。本综述系统阐述了KRAS突变结直肠癌的分子机制、当前进展与挑战，并对未来治疗前景进行了展望。
Targeting the KRAS Oncogene for Patients with Metastatic Colorectal Cancer
肿瘤(癌症)患者之家