对非活性状态选择性 RASG12C 抑制剂的耐药性通常需要 RASGTP 的积累，因此可能需要有效抑制活性 RAS。在这里，我们评估了 RAS(ON) 多选择性三复合物抑制剂 RMC-7977 的抗肿瘤活性，并剖析了 KRASG12C 突变 NSCLC 中的反应和耐受机制。广谱、可逆的 RASGTP 抑制，无论是否同时共价靶向活性 RASG12C，在原发性或获得性 RASG12C(ON) 或 (OFF) 抑制剂耐药性的多种共突变 KRASG12C 突变 NSCLC 小鼠模型中产生了卓越且差异化的抗肿瘤活性。对时间分辨单细胞转录反应的研究建立了 NSCLC 生态系统中多模式急性和慢性 RAS 通路抑制的体内图谱，并揭示了支持肿瘤细胞长期存留的再生粘液转录程序。在晚期 KRASG12C 突变 NSCLC 患者中，粘液性组织学特征的存在预示着对索托拉西或阿达拉西的反应不佳。我们的结果对个性化医疗和合理的 RAS 抑制剂锚定治疗策略的开发具有潜在影响。

Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. Broad-spectrum, reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse co-mutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or (OFF) inhibitor resistance. Interrogation of time-resolved single cell transcriptional responses established an in vivo atlas of multi-modal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histological features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.