KRAS 突变 NSCLC 对活性 RAS 抑制剂的反应和耐受机制。

IF 29.7 1区 医学 Q1 ONCOLOGY
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, Ferdinandos Skoulidis
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引用次数: 0

摘要

对非活性状态选择性 RASG12C 抑制剂的抗药性经常会导致 RASGTP 的积累,因此有效抑制活性 RAS 可能是可取的。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 的反应和耐受机制。在原发性或获得性 RASG12C(ON)或(OFF)抑制剂耐药性的各种共突变 KRASG12C 突变 NSCLC 小鼠模型中,广谱、可逆的 RASGTP 抑制与或不同时共价靶向活性 RASG12C 可产生卓越的差异化抗肿瘤活性。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,并发现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NSCLC患者中,粘液组织学特征的存在预示着患者对索拉西布或阿达拉西布的反应不佳。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有潜在的意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mechanisms of Response and Tolerance to Active RAS Inhibition in KRAS-Mutant Non-Small Cell Lung Cancer.

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) multiselective 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 comutational 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. Significance: Our work reveals robust and durable antitumor activity of the preclinical RAS(ON) multiselective 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. See related commentary by Marasco and Misale, p. 2018.

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来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
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