KRAS^(G12C)抑制剂抗肿瘤耐药机制及克服策略研究进展

Recent advances in mechanisms of KRAS^(G12C) inhibitors anti-tumor resistance and relevant overcoming strategies

KRAS是人类癌症中最常出现突变的致癌基因之一。尽管长期以来诸多研究致力于直接或间接靶向KRAS的干预策略研究,但仍面临难以靶向、效果受限的问题,因此KRAS一直被认为是“不可成药”的靶点蛋白。最近,KRAS^(G12C)突变亚型特异性抑制剂研究取得重大突破,部分KRAS^(G12C)抑制剂相继进入临床试验,包括阿达格拉西布(adagrasib)和索托拉西(sotorasib)等,且已显示出显著的疗效,为KRAS^(G12C)突变驱动的恶性肿瘤患者带来了希望。RAS通路其他抑制剂的研发经验表明,快速产生的耐药性会限制药物的作用,而目前研究已经发现KRAS^(G12C)抑制剂亦存在明显的耐药问题。本文概述KRAS^(G12C)抑制剂的研发现状,讨论其耐药的机制,为探索克服其耐药的干预策略提供思路和方向。

KRAS is one of the most frequently mutated human oncogenes.In spite of mounting efforts on the development of direct or indirect inhibition targeting KRAS,little has been achieved because of insurmountable difficulties,titling KRAS"undruggable".Recently,subtype-specific inhibitors have shown great hope.Some KRAS^(G12C)inhibitors have entered clinical trials,including adagrasib and sotorasib,and have shown preliminary clinical effectiveness.Experiences from the inhibitors targeting the downstream factors of RAS pathways show that the anticancer activity of these drugs will be limited due to the development of drug resistance.Preclinical studies of KRAS^(G12C)inhibitors have revealed that the application of these agents might be hampered by the drug resistance issue.The current review aims to describe the current status of KRAS^(G12C)inhibitors,and discuss the mechanisms underlying KRAS^(G12C)inhibitor resistance,so as to provide the clues for the combat of drug resistance.