Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRAS^G12C, the most common mutation, is found in ∼13% of patients. While KRAS was long considered ‘undruggable’, several novel direct KRAS^G12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.

非小细胞肺癌 (NSCLC) 是癌症死亡的主要原因。大约三分之一的 NSCLC 患者具有 KRAS 突变。KRAS ^G12C是最常见的突变，在约 13% 的患者中发现。虽然 KRAS 长期以来被认为“不可成药”，但几种新型直接 KRAS ^G12C抑制剂在 I/II 期试验中显示出令人鼓舞的疗效迹象，其中之一（索托拉西）最近已获得美国食品和药物管理局的批准。本综述探讨了 KRAS 突变在 NSCLC 中的作用以及靶向 KRAS 的挑战。基于特定的 KRAS 生物学，它报告了令人振奋的进展，探索使用新型直接 KRAS 抑制剂作为单一疗法或与其他靶向疗法、化学疗法和免疫疗法联合使用。