KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRASG12C inhibitors are currently changing the treatment paradigm for patients with KRASG12C-mutated non–small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRASG12D-, KRASG12V-, KRASG13D-, KRASG12R-, and KRASG12A-mutant or KRAS wild-type–amplified cancers, as well as cancers with acquired resistance to KRASG12C inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility. Significance: Mutant-selective KRASG12C inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRAS-driven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.

中文翻译：

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通过对所有 KRAS 突变体进行药物治疗来扩大精准肿瘤学的范围


KRAS 是最常突变的癌基因，大约七分之一的癌症中都存在突变。等位基因特异性 KRASG12C 抑制剂目前正在改变 KRASG12C 突变非小细胞肺癌和结直肠癌患者的治疗模式。解决以前难以捉摸的 KRAS 等位基因的成功推动了所有 KRAS 突变体的药物发现工作。泛 KRAS 药物有潜力治疗广泛的患者群体，包括 KRASG12D、KRASG12V、KRASG13D、KRASG12R 和 KRASG12A 突变或 KRAS 野生型扩增的癌症，以及对 KRASG12C 抑制剂获得性耐药的癌症。在这里，我们回顾了积极追求的等位基因特异性和泛 KRAS 抑制策略及其潜在效用。意义：突变选择性 KRASG12C 抑制剂针对所有 KRAS 驱动的癌症中的一小部分（约 13.6%）。需要广泛的 KRAS 药物来全面征服 KRAS 驱动的癌症。从概念上讲，我们预见未来两类 KRAS 药物：针对个体变异等位基因的突变选择性 KRAS 药物和针对广泛 KRAS 改变的泛 KRAS 疗法。