Kras突变与肿瘤发生及治疗

Kras Mutation in Tumorigenesis and Cancer Therapy

RAS蛋白是一类与GTP/GDP结合并具有GTP水解酶活性的小G蛋白。作为分子开关,RAS通过结合GTP而激活下游MAPK及PI3K-AKT等信号通路,从而调控细胞生长、增殖、分化和凋亡等生命过程,其突变与癌症发生发展密切相关。KRAS是RAS家族中最常见的突变类型。Kras突变将导致其丧失GTP水解酶活性,从而持续激活下游信号通路,促使细胞增殖失控而癌变;同时,Kras突变是肿瘤细胞的维持生长增殖所必需条件,也是肿瘤获得性耐药的关键原因之一。然而迄今为止,临床上尚无有效治疗Kras突变肿瘤的药物,探索针对Kras突变肿瘤的有效治疗策略与方法也成为近年来的研究热点。该文从KRAS的功能、信号通路、突变与肿瘤的关系及目前Kras突变肿瘤的不同治疗策略和研究现状进行简要综述。

RAS proteins belong to a superfamily of small GTPase that act as molecular switch to control cell growth, proliferation, senescence and apoptosis by activating multiple downstream signaling pathways, including MAPK and PI3K-AKT. The mutation of RAS is tightly correlated with tumorigenesis. KRAS is the isoform most frequently mutated in RAS-driven cancers. Once mutated, KRAS will lose its GTP hydrolase activities and continues to activate its downstream signals, thereby driving tumorigenesis. The existence of Kras mutant is not only necessary for tumor maintenance, but one of the key mechanisms of tumor acquired drug resistance. Therefore, KRAS is a useful drug target for cancer therapy. Unfortunately, up to now, there are still no effective pharmacological inhibitors of KRAS developed in clinic. Exploring the effective treatment strategies and methods for Kras mutant tumors has become a hot research topic in recent years. Here, we briefly review the functions of KRAS, its downstream signaling pathways, the relationship between Kras mutation and tumorigenesis, and the current treatment strategies of Kras mutations.