Kirsten rat sarcoma virus (KRAS) is the most frequently found oncogene in human cancers, including non-small-cell lung cancer (NSCLC). For many years, KRAS was considered “undruggable” due to its structure and difficult targeting. However, the discovery of the switch II region in the KRAS-G12C-mutated protein has changed the therapeutic landscape with the design and development of novel direct KRAS-G12C inhibitors. Sotorasib and adagrasib are FDA-approved targeted agents for pre-treated patients with KRAS-G12C-mutated NSCLC. Despite promising results, the efficacy of these novel inhibitors is limited by mechanisms of resistance. Ongoing studies are evaluating combination strategies for overcoming resistance. In this review, we summarize the biology of the KRAS protein and the characteristics of KRAS mutations. We then present current and emerging therapeutic approaches for targeting KRAS mutation subtypes intending to provide individualized treatment for lung cancer harboring this challenging driver mutation.
Kirsten大鼠肉瘤病毒（KRAS）是人类癌症中最常见的致癌基因，包括非小细胞肺癌（NSCLC）。多年来，由于其结构和靶向难度，KRAS一直被视为“不可成药”靶点。然而，KRAS-G12C突变蛋白中开关II区域的发现改变了治疗格局，推动了新型直接KRAS-G12C抑制剂的设计与开发。Sotorasib和adagrasib是FDA批准用于经治KRAS-G12C突变NSCLC患者的靶向药物。尽管疗效显著，但这些新型抑制剂的效果受到耐药机制的限制。目前正在进行的研究正在评估克服耐药的联合策略。本综述总结了KRAS蛋白的生物学特性及KRAS突变特征，并系统阐述了针对KRAS突变亚型的现有及新兴治疗方法，旨在为携带这一挑战性驱动突变的肺癌患者提供个体化治疗策略。
Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer
肿瘤(癌症)患者之家