SCI
11 October 2024
Mechanisms of Response and Tolerance to Active RAS Inhibition in KRAS-Mutant Non–Small Cell Lung Cancer
(Cancer Discovery, IF: 29.7)
Haniel A. Araujo, Ximo Pechuan-Jorge, Teng Zhou, Minh Truong Do, Xin Hu, Frank R. Rojas Alvarez, Maria E. Salvatierra, Heladio P. Ibarguen, Richard Lee, Rashi Raghulan, Harshit Shah, Mariela A. Moreno Ayala, Kevin Chen, Nataliya Tovbis Shifrin, Shuhong Wu, Luisa M. Solis Soto, Marcelo V. Negrao, Don L. Gibbons, David S. Hong, Jack A. Roth, John V. Heymach, Jianjun Zhang, Jingjing Jiang, Mallika Singh, Jacqueline A.M. Smith, Elsa Quintana, and Ferdinandos Skoulidis
CORRESPONDENCE TO: fskoulidis@mdanderson.org
Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the antitumor activity of the RAS(ON) multi selective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non–small cell lung cancer (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 RASG12C(OFF) inhibitor resistance. Interrogation of time-resolved single-cell transcriptional responses established an in vivo atlas of multimodal 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 histologic 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.
对非活性状态选择性 RASG12C 抑制剂的耐药性通常会导致 RASGTP 的积累，从而可能需要有效抑制活性RAS。在此，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，并分析了其在 KRASG12C- 突变非小细胞肺癌（NSCLC）的反应和耐受机制。广谱可逆 RASGTP 抑制，同时或不同时共价靶向活性 RASG12C，在原发性或获得性 RASG12C(ON) 或 RASG12C(OFF) 抑制剂抗性的多种共突变 KRASG12C 突变NSCLC小鼠模型中产生了优异和分化的抗肿瘤活性。对时间分辨单细胞转录反应的研究中建立了NSCLC生态系统中多模式的急性和慢性RAS通路抑制的体内图谱，并揭示了支持肿瘤细胞长期存在的再生粘液转录程序。在晚期 KRASG12C 突变型非小细胞肺癌患者中，粘液组织学特征的存在预示着对Sotorasib或Adagrasib的反应不佳。我们的研究结果对个性化医疗和开发合理的RAS抑制剂锚定治疗策略具备有潜力的意义。
Our work reveals robust and durable antitumor activity of the preclinical RAS(ON) multi-selective inhibitor RMC-7977 against difficult-to-treat subsets of KRASG12C-mutant NSCLC with primary or acquired RASG12C inhibitor resistance and identifies a conserved mucinous transcriptional state that supports RAS inhibitor tolerance.
我们的工作揭示了临床前RAS（ON）多选择性抑制剂RMC-7977对具有原发性或获得性RASG12C 抑制剂耐药性的难治 KRASG12C 突变NSCLC亚群的强大和持久的抗肿瘤活性，并鉴定了一种支持RAS抑制剂耐受的保守粘液转录状态。
