The three RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in cancer. KRAS is the predominant isoform mutated in cancer and is most prevalently mutated in major causes of cancer deaths including lung, colorectal, and pancreatic cancers. Despite extensive academic and industry efforts to target KRAS, it would take nearly four decades before approval of the first clinically effective KRAS inhibitors for the treatment of KRAS mutant lung cancer. We revisit past anti-KRAS strategies and painful lessons learned and then focus on the rapidly evolving landscape of direct RAS inhibitors, resistance mechanisms, and potential combination treatments.

中文翻译：

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“不可成药的 KRAS”：毕竟是可成药的


三个 RAS 基因 （HRAS、KRAS 和 NRAS） 构成了癌症中最常突变的癌基因家族。KRAS 是癌症中突变的主要亚型，在癌症死亡的主要原因中突变最普遍，包括肺癌、结直肠癌和胰腺癌。尽管学术界和工业界为靶向 KRAS 做出了广泛的努力，但第一个临床有效的 KRAS 抑制剂用于治疗 KRAS 突变肺癌需要近四十年的时间才能获得批准。我们回顾了过去的抗 KRAS 策略和痛苦的教训，然后专注于直接 RAS 抑制剂、耐药机制和潜在联合治疗的快速发展前景。