KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging. Among the different known mutants, KRas^G12C has been proved to be successfully targeted recently. Several covalent inhibitors selectively targeting KRas^G12C have shown promising efficacy against cancers harboring KRAS^G12C mutation in clinical trials and AMG510 (sotorasib) has been approved for the treatment of KRAS^G12C-mutated locally advanced or metastatic non-small cell lung cancer. However, the overall responsive rate of KRas^G12C inhibitors was around 50% in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable. It is of great importance to discover biomarkers to distinguish patients who are likely benefitted. Moreover, adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies. Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRas^G12C inhibitors in preclinical settings. This review summarized the recent progress of covalent KRas^G12C inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.

KRAS是癌症中最常见的突变癌基因之一，直接针对 KRas 的治疗一直具有挑战性。在不同的已知突变体中，最近已证明 KRas ^G12C已成功靶向。几种选择性靶向 KRas ^G12C的共价抑制剂在临床试验中显示出对携带KRAS ^G12C突变的癌症有希望的疗效，AMG510 (sotorasib) 已被批准用于治疗KRAS ^G12C突变的局部晚期或转移性非小细胞肺癌。不过KRas ^{G12C的整体响应速度}抑制剂在非小细胞肺癌患者中约占 50%，而在结直肠癌或阑尾癌患者中的疗效似乎不太理想。发现生物标志物以区分可能受益的患者非常重要。此外，与其他分子靶向治疗一样，持续给药不可避免地会出现适应性耐药。^{已经研究了几种组合方案以努力增强 KRas G12C}抑制剂在临床前环境中的功效。^{本综述总结了共价 KRas G12C}抑制剂的最新进展，重点是识别生物标志物以预测或监测疗效，并在阐明耐药机制的基础上提出合理的药物组合。