KRAS突变结直肠癌相关治疗的研究进展

doi:10.19401/j.cnki.1007-3639.2024.10.008

摘要/Abstract

摘要：

Kirsten大鼠肉瘤病毒癌基因同源物（Kirsten rats arcomaviral oncogene homolog，KRAS）是一类与肿瘤关系密切的基因，其表达水平的高低是提示肿瘤患者预后、放化疗效果等的重要指标。RAS突变是人类肿瘤中最为常见的致癌驱动突变，其中KRAS突变占比高达85%。KRAS突变位置主要集中在第12、13、61、146位密码子。密码子G12作为4个热点中突变频率最高的密码子又分为多种亚型，其中G12D突变最常见，其次是G12V、G12C等。结直肠癌（colorectal cancer，CRC）是KRAS突变频率较高的肿瘤之一。G12D和G12V是CRC中常见的两种突变亚型。KRAS^G12C抑制剂上市之后，其他靶向治疗药物也相继进入临床试验阶段。本研究总结KRAS基因突变的结直肠癌临床研究领域的新进展，包括靶向治疗药物、化疗药物、免疫治疗药物、细胞毒类药物、铁死亡及其他治疗方法研究的最新进展等。其中，在靶向治疗药物方面，本综述探讨了KRAS^G12C抑制剂（sotorasib、adagrasib、D-1553、IBI351等）、抗血管生成药物（单克隆抗体如贝伐珠单抗、雷莫芦单抗等）、小分子多靶点酪氨酸激酶抑制剂如舒尼替尼等的临床应用。而在免疫治疗药物方面，亦有诸多进展，如ARETHUSA临床试验发现，替莫唑胺使O-6-甲基鸟嘌呤-DNA甲基转移酶（O-6-methylguanine-DNA methyltransferase，MGMT）缺失、RAS突变的晚期转移性结直肠癌（metastatic colorectal cancer，mCRC）患者的肿瘤突变负荷（tumor mutational burden，TMB）增大，为患者的免疫治疗提供了创新性思路；再如信迪利单抗联合贝伐珠单抗、奥沙利铂和卡培他滨可用于一线治疗RAS突变、微卫星稳定（microsatellite stability，MSS）、不可切除的mCRC。相关研究显示联合用药有较好的治疗潜力和可控的安全耐受性。本综述通过探讨KRAS突变的机制及临床研究及治疗的最新进展，以期为KRAS突变结直肠癌的治疗提供参考。

关键词: Kirsten大鼠肉瘤病毒癌基因同源物, 结直肠癌, 药物治疗

Abstract:

Kirsten rat sarcoma viral oncogene homolog (KRAS) is a type of gene closely related to human tumors. And it’s an important medical index to access the tumor development, prognosis and the efficacy of chemoradiotherapy. RAS mutations, in which KRAS mutations account for up to 85%, are the most common oncogenic driving mutations in human tumors. The most frequent KRAS mutation sites are codons 12, 13, 61 and 146. Codon G12, as the most frequently mutated one, can be divided into multiple subtypes, with G12D mutation being the most common, followed by G12V, G12C, etc. Colorectal cancer (CRC) is one of the tumors with the highest frequency of KRAS mutations. Both G12D and G12V are the most common mutation subtypes in CRC. In the field of treatments for CRC with KRAS mutations, targeted therapy had not been possible until the release of KRAS^G12C inhibitors in 2013, and new drugs have been developed one after another since then. This study summarized the mutations of KRAS and the advances in clinical research, including the latest advances in targeted drugs, chemotherapy drugs, immunotherapy drugs, ferroptosis, and other treatment methods. Among them, in terms of targeted drugs, this review explored KRAS^G12C inhibitors (sotorasib, adagrasib, D-1553, IBI351, etc.), anti-angiogenic drugs (monoclonal antibodies such as bevacizumab, remdesizumab, etc), small molecule multi-target tyrosine kinase inhibitors such as sunitinib, etc. In terms of immunotherapy drugs, there have also been many advances, such as the ARETHUSA clinical trial, which found that temozolomide reduced the tumor mutational burden (TMB) of O-6-methylguanine-DNA methyltransferase (MGMT) deficiency and RAS mutation in patients with advanced metastatic colorectal cancer (mCRC), providing innovative ideas for patient immunotherapy. For example, the combination of xindilimab with bevacizumab, oxaliplatin, and capecitabine can be used for first-line treatment of RAS mutations, microsatellite stability (MSS), and unresectable mCRC. Relevant studies have shown that the combination therapy has good therapeutic potential and controllable tolerability safety. This review explored the mechanisms of KRAS mutations and the latest advances in clinical research and treatment, in order to provide reference for the treatment of KRAS mutated colorectal cancer.

Key words: Kirsten rats arcomaviral oncogene homolog, Colorectal cancer, Medication

中图分类号:

R735.3+4

张少华, 黎哲宁, 王薇, 卫奕凡, 洪永刚, 郝立强. KRAS突变结直肠癌相关治疗的研究进展[J]. 中国癌症杂志, 2024, 34(10): 979-986.

ZHANG Shaohua, LI Zhening, WANG Wei, WEI Yifan, HONG Yonggang, HAO Liqiang. Research progress in the related treatment of KRAS mutant colorectal cancer[J]. China Oncology, 2024, 34(10): 979-986.

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