Lung cancer remains the leading cause of cancer-related deaths in men and women worldwide, and 85% of these patients have non-small cell lung cancer. In recent years, the clinical use of targeted drug therapy and immune checkpoint inhibitors has dramatically changed the treatment landscape for advanced NSCLC. The mechanism and the value of targeted therapies have been a hot topic of research, as KRAS is one of the earliest discovered and most frequently mutated oncogenes, which is activated by binding to GTP and triggers a series of cascade reactions in cell proliferation and mitosis. The KRAS protein acts as a molecular switch and is activated by binding to GTP, triggering a series of cascade responses in cell proliferation and mitosis. Clinically, patients with KRAS mutated NSCLC have poor response to systemic medical therapy and poor prognosis. Since the first report of KRAS gene in 1982, research on KRAS targeted therapeutics has been slow, and previous studies such as farnesyltransferase inhibitors and downstream protein inhibitors of KRAS signaling pathway have not achieved the expected results, making KRAS long defined as a "non-druggable target". The deeper understanding of the crystal structure of KRAS has led to the discovery of potential therapeutic sites for KRAS and the development of several drugs directly targeting KRAS, especially KRAS G12C inhibitors such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have shown encouraging results in clinical trials. In recent years, studies on the therapeutic efficacy of immune checkpoint inhibitors for KRAS-mutated NSCLC have made some progress. In this review, we systematically introduce the basic understanding of RAS gene and clinical characteristics of KRAS mutated NSCLC patients, summarize the medical treatments for KRAS mutated NSCLC, including chemotherapy, anti-vascular drug therapy and tumor immunotherapy, and focus on the review and outlook of the research progress of KRAS targeted therapy.
近年来，靶向药物治疗和免疫检查点抑制剂的临床应用极大地改变了晚期非小细胞肺癌(NSCLC)的治疗格局。表皮生长因子受体和间变性淋巴瘤受体酪氨酸激酶等驱动基因改变NSCLC的TKI靶向治疗均已取得了良好临床疗效，而Kirsten大鼠肉瘤病毒基因同源物(KRAS)作为较早发现和突变频率较高的癌基因之一，其靶向药物治疗研究进展缓慢，法尼基转移酶抑制剂、KRAS信号通路下游蛋白抑制剂等靶向治疗研究均未取得预期结果，使得KRAS长期以来被定义为"不可成药的靶点"。KRAS蛋白作为分子开关，通过与三磷酸鸟苷结合而被激活，引发系列级联反应，在细胞增殖和有丝分裂中发挥作用。KRAS突变的NSCLC患者对内科系统性治疗反应性差，预后不佳。随着对KRAS晶体结构认识的不断深入，研究者发现了KRAS潜在的治疗位点，进而开发出了多个直接针对KRAS的靶向药物，尤其是KRAS G12C抑制剂，如AMG510(sotorasib)和MRTX849(adagrasib)，其临床试验获得了令人鼓舞的结果。文章在系统介绍KRAS突变NSCLC患者临床特征及内科治疗方法的基础上，重点就KRAS靶向治疗的研究进展进行了总结和展望。.
Keywords: Carcinoma, non-small-cell lung; Kirsten rat sarcoma viral oncogene homolog; Target therapy.