RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 61¹. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer^2,3. Nevertheless, KRAS^G12C mutations account for only around 15% of KRAS-mutated cancers^4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRAS^G12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRAS^G12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

RAS 癌基因（统称为NRAS、HRAS，尤其是KRAS）是癌症中最常突变的基因之一，常见的驱动突变发生在密码子 12、13 和 61 ¹处。 KRAS(G12C) 癌蛋白的小分子抑制剂已在多种癌症类型患者中证明了临床疗效，并已获得监管部门批准用于治疗非小细胞肺癌^2,3。然而，KRAS ^G12C突变仅占KRAS突变癌症的 15% 左右^{4,5 ，并且对于大多数含有其他常见}KRAS突变的肿瘤患者，尚无批准的 KRAS 抑制剂。在这里，我们描述了 RMC-7977，一种可逆的三复合物 RAS 抑制剂，对突变型和野生型 KRAS、NRAS 和 HRAS 变体的活性状态具有广谱活性（RAS(ON) 多选择性抑制剂）。临床前，RMC-7977 表现出对携带各种 RAS 基因型的 RAS 成瘾肿瘤的有效活性，特别是针对具有KRAS密码子 12 突变 ( KRAS ^G12X ) 的癌症模型。 RMC-7977 治疗可导致肿瘤消退，并且在各种 RAS 成瘾的临床前癌症模型中具有良好的耐受性。此外，RMC-7977 可抑制KRAS ^G12C癌症模型的生长，这些模型由于 RAS 通路信号传导的恢复而对 KRAS(G12C) 抑制剂具有抗性。因此，RAS(ON)多选择性抑制剂可以针对多种致癌和野生型RAS亚型，并有可能治疗多种RAS成瘾性癌症，而这些癌症的临床需求尚未得到满足。一种相关的 RAS(ON) 多选择性抑制剂 RMC-6236 目前正在KRAS突变实体瘤患者中进行临床评估（ClinicalTrials.gov 标识符：NCT05379985）。