Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered ‘undruggable’ owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRAS^G12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.

尽管 KRAS 是实体瘤中最常改变的致癌蛋白，但由于突变亚型内缺乏药理学可靶向的口袋，KRAS 在历史上一直被认为是“不可治疗的”。然而，药物设计的改进最终导致了对处于活性或非活性状态的突变 KRAS 具有选择性的抑制剂的开发。其中一些抑制剂已证明对KRAS ^G12C患者有效- 突变癌症，并已成为改变实践。与这些进展相关的兴奋因耐药性而减弱，这限制了对这些药物反应的深度和/或持续时间。我们对癌细胞和肿瘤微环境中 RAS 信号传导的理解的改进表明了几种新型联合疗法的潜力，这些疗法目前正在临床试验中进行探索。在此，我们概述了 RAS 通路，并回顾了针对致癌 RAS 的治疗策略的发展和现状，以及它们改善 RAS 突变恶性肿瘤患者预后的潜力。然后，我们讨论了抵抗机制和策略带来的挑战，这些挑战可能会被克服。