KRAS G12C突变在结直肠癌中的耐药机制及联合治疗策略  

Mechanism of drug resistance to KRAS G12C mutation in colorectal cancer and the combination treatment strategy

作　　者：冯旭娇 陈杨 李一林[1] 张子震 沈琳[1] 李健 Feng Xujiao;Chen Yang;Li Yilin;Zhang Zizhen;Shen Lin;Li Jian(Department of Gastrointestinal Oncology,State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers,Beijing Key Laboratory of Carcinogenesis and Translational Research,Peking University Cancer Hospital&Institute,Beijing 100142,China)

机构地区：[1]北京大学肿瘤医院暨北京市肿瘤防治研究所消化肿瘤内科,消化系肿瘤整合防治全国重点实验室,恶性肿瘤转化研究北京市重点实验室,北京100142

出　　处：《肿瘤综合治疗电子杂志》2024年第1期134-141,共8页Journal of Multidisciplinary Cancer Management(Electronic Version)

基　　金：国家自然科学基金项目(82373252)。

摘　　要：KRAS突变是人类肿瘤中最常见的致癌突变之一,占RAS突变的85%左右。人类35%~49%的结直肠癌(colorectal cancer,CRC)和20%~30%的非小细胞肺癌均是KRAS基因突变驱动的。在KRAS G12C突变的研究中发现一个可靶向的半胱氨酸位点,靶向KRAS G12C的新药sotorasib、adagrasib相继开展了临床研究,但在治疗过程中发现肺癌和CRC患者对药物的应答情况不同,治疗相关的耐药机制也存在差异。本文旨在阐述KRAS G12C突变在CRC的固有耐药机制和获得性耐药机制,包括治疗后继发KRAS改变、KRAS上下游信号通路反馈激活、上皮间质转化、细胞周期失调以及免疫抑制等获得性耐药机制,以及克服CRC耐药的多种联合治疗方案,以期实现临床最大获益和改善患者预后。KRAS mutation is the most common oncogenic mutation in human tumors,accounting for about 85%of RAS mutations.35%-49%of colorectal cancer(CRC)and 20%-30%of non-small cell lung cancer in humans are driven by KRAS mutations.A L-cysteine site has been identified in the study of KRAS G12C mutation,and the new drugs sotorasib and adagrasib targeting KRAS G12C have been studied.However,during the course of treatment,it was found that the patients with lung cancer and CRC had different responses to the drugs,and the drug-resistance mechanisms related to treatment were also different.This paper focuses on the inherent and acquired resistance mechanisms of KRAS G12C mutation in CRC,including secondary KRAS gene change after treatment,feedback activation of upstream and downstream signaling pathways of KRAS,epithelial interstitial transformation,cell cycle disorder,and immunosuppression.Finally,a variety of combination therapy schemes to overcome drug resistance in CRC are reviewed in order to achieve maximum clinical benefit and improve the prognosis of patients.

关 键 词：结直肠癌 KRAS G12C突变 耐药机制 联合治疗 

分 类 号：R735.3[医药卫生—肿瘤]