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

Matthew Holderfield, Bianca J. Lee, Jingjing Jiang, Aidan Tomlinson, Kyle J. Seamon, Alessia Mira, Enrico Patrucco, Grace Goodhart, Julien Dilly, Yevgeniy Gindin, Nuntana Dinglasan, Yingyun Wang, Lick Pui Lai, Shurui Cai, Lingyan Jiang, Nicole Nasholm, Nataliya Shifrin, Cristina Blaj, Harshit Shah, James W. Evans, Nilufar Montazer, Oliver Lai, Jade Shi, Ethan Ahler, Elsa Quintana, Stephanie Chang, Anthony Salvador, Abby Marquez, Jim Cregg, Yang Liu, Anthony Milin, Anqi Chen, Tamar Bar Ziv, Dylan Parsons, John E. Knox, Jennifer E. Klomp, Jennifer Roth, Matthew Rees, Melissa Ronan, Antonio Cuevas-Navarro, Feng Hu, Piro Lito, David Santamaria, Andrew J. Aguirre, Andrew M. Waters, Channing J. Der, Chiara Ambrogio, Zhengping Wang, Adrian L. Gill, Elena S. Koltun, Jacqueline A. M. Smith (), David Wildes () and Mallika Singh ()
Additional contact information
Matthew Holderfield: Revolution Medicines
Bianca J. Lee: Revolution Medicines
Jingjing Jiang: Revolution Medicines
Aidan Tomlinson: Revolution Medicines
Kyle J. Seamon: Revolution Medicines
Alessia Mira: University of Torino
Enrico Patrucco: University of Torino
Grace Goodhart: University of Cincinnati
Julien Dilly: Dana-Farber Cancer Institute
Yevgeniy Gindin: Revolution Medicines
Nuntana Dinglasan: Revolution Medicines
Yingyun Wang: Revolution Medicines
Lick Pui Lai: Revolution Medicines
Shurui Cai: Revolution Medicines
Lingyan Jiang: Revolution Medicines
Nicole Nasholm: Revolution Medicines
Nataliya Shifrin: Revolution Medicines
Cristina Blaj: Revolution Medicines
Harshit Shah: Revolution Medicines
James W. Evans: Revolution Medicines
Nilufar Montazer: Revolution Medicines
Oliver Lai: Revolution Medicines
Jade Shi: Revolution Medicines
Ethan Ahler: Revolution Medicines
Elsa Quintana: Revolution Medicines
Stephanie Chang: Revolution Medicines
Anthony Salvador: Revolution Medicines
Abby Marquez: Revolution Medicines
Jim Cregg: Revolution Medicines
Yang Liu: Revolution Medicines
Anthony Milin: Revolution Medicines
Anqi Chen: Revolution Medicines
Tamar Bar Ziv: Revolution Medicines
Dylan Parsons: Revolution Medicines
John E. Knox: Revolution Medicines
Jennifer E. Klomp: University of North Carolina at Chapel Hill
Jennifer Roth: Broad Institute of MIT and Harvard
Matthew Rees: Broad Institute of MIT and Harvard
Melissa Ronan: Broad Institute of MIT and Harvard
Antonio Cuevas-Navarro: Memorial Sloan Kettering Cancer Center
Feng Hu: Memorial Sloan Kettering Cancer Center
Piro Lito: Memorial Sloan Kettering Cancer Center
David Santamaria: CSIC–Universidad de Salamanca
Andrew J. Aguirre: Dana-Farber Cancer Institute
Andrew M. Waters: University of Cincinnati
Channing J. Der: University of North Carolina at Chapel Hill
Chiara Ambrogio: University of Torino
Zhengping Wang: Revolution Medicines
Adrian L. Gill: Revolution Medicines
Elena S. Koltun: Revolution Medicines
Jacqueline A. M. Smith: Revolution Medicines
David Wildes: Revolution Medicines
Mallika Singh: Revolution Medicines

Nature, 2024, vol. 629, issue 8013, 919-926

Abstract: Abstract 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 611. 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 cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, 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 (KRASG12X). 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 KRASG12C 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).

Date: 2024
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DOI: 10.1038/s41586-024-07205-6

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