Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy

• 成果类型: Article
• 署名作者: Holderfield, Matthew; Lee, Bianca J.; Jiang, Jingjing; Tomlinson, Aidan; Seamon, Kyle J.; Mira, Alessia; Patrucco, Enrico; Goodhart, Grace; Dilly, Julien; Gindin, Yevgeniy; Dinglasan, Nuntana; Wang, Yingyun; Lai, Lick Pui; Cai, Shurui; Jiang, Lingyan; Nasholm, Nicole; Shifrin, Nataliya; Blaj, Cristina; Shah, Harshit; Evans, James W.; Montazer, Nilufar; Lai, Oliver; Shi, Jade; Ahler, Ethan; Quintana, Elsa; Chang, Stephanie; Salvador, Anthony; Marquez, Abby; Cregg, Jim; Liu, Yang; Milin, Anthony; Chen, Anqi; Ziv, Tamar Bar; Parsons, Dylan; Knox, John E.; Klomp, Jennifer E.; Roth, Jennifer; Rees, Matthew; Ronan, Melissa; Cuevas-Navarro, Antonio; Hu, Feng; Lito, Piro; Santamaria, David; Aguirre, Andrew J.; Waters, Andrew M.; Der, Channing J.; Ambrogio, Chiara; Wang, Zhengping; Gill, Adrian L.; Koltun, Elena S.; Smith, Jacqueline A. M.; Wildes, David; Singh, Mallika
• 署名单位: University of Turin; University System of Ohio; University of Cincinnati; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; University of North Carolina; University of North Carolina Chapel Hill; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; University of Salamanca; Consejo Superior de Investigaciones Cientificas (CSIC); Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of North Carolina; University of North Carolina Chapel Hill; University System of Ohio; University of Cincinnati
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6622
• DOI: 10.1038/s41586-024-07205-6
• 发表日期: 2024-05-23
• 关键词: acquired-resistance; kras; braf

摘要

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 61(1). 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).