Mechanisms of response and tolerance to active RAS inhibition in KRAS-mutant NSCLC

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. Overall design: Lung tumor cell lines derived from KRAS G12C mutated C57/BL6 mice mice were grown in vivo and treated with either vehicle or RAS inhibitors. Tumors were processed isolate cells for scRNAseq.

对非活性状态选择性RASG12C抑制剂产生耐药性的过程，常伴随RASGTP的蓄积，这使得靶向活性RAS的有效抑制策略具备潜在应用价值。本研究评估了RAS(ON)多选择性三复合物抑制剂RMC-7977的抗肿瘤活性，并解析了KRASG12C突变型非小细胞肺癌（Non-Small Cell Lung Cancer, NSCLC）中应答与耐受的分子机制。无论是否同时联合靶向活性RASG12C的共价抑制手段，广谱可逆的RASGTP抑制策略，在携带原发性或获得性RASG12C(ON)或(OFF)抑制剂耐药的多种共突变KRASG12C突变型非小细胞肺癌小鼠模型中，均展现出更优异且独特的抗肿瘤活性。通过对时间分辨率下单细胞转录应答的系统解析，我们构建了非小细胞肺癌微环境中多模态急性与慢性RAS通路抑制的体内图谱，并揭示了一种可支持肿瘤细胞长期存续的再生性黏液样转录程序。在晚期KRASG12C突变型非小细胞肺癌患者中，黏液样组织学特征的存在预示着对索托拉西布（sotorasib）或阿达格拉西布（adagrasib）的应答不佳。本研究结果为个体化医疗以及以RAS抑制剂为核心的合理化治疗策略开发提供了潜在指导。整体实验设计：将源自KRAS G12C突变型C57/BL6小鼠的肺肿瘤细胞系进行体内定植，随后分别给予赋形剂对照或RAS抑制剂处理。对肿瘤组织进行处理以分离细胞，用于单细胞RNA测序（single-cell RNA sequencing, scRNAseq）。