2. Academic Validation
  3. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy

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

  • Nature. 2024 Apr 8. doi: 10.1038/s41586-024-07205-6.
Matthew Holderfield 1,  Bianca J Lee 1,  Jingjing Jiang 1,  Aidan Tomlinson 1,  Kyle J Seamon 1,  Alessia Mira 2,  Enrico Patrucco 2,  Grace Goodhart 3,  Julien Dilly 4,  Yevgeniy Gindin 1,  Nuntana Dinglasan 1,  Yingyun Wang 1,  Lick Pui Lai 1,  Shurui Cai 1,  Lingyan Jiang 1,  Nicole Nasholm 1,  Nataliya Shifrin 1,  Cristina Blaj 1,  Harshit Shah 1,  James W Evans 1,  Nilufar Montazer 1,  Oliver Lai 1,  Jade Shi 1,  Ethan Ahler 1,  Elsa Quintana 1,  Stephanie Chang 1,  Anthony Salvador 1,  Abby Marquez 1,  Jim Cregg 1,  Yang Liu 1,  Anthony Milin 1,  Anqi Chen 1,  Tamar Bar Ziv 1,  Dylan Parsons 1,  John E Knox 1,  Jennifer E Klomp 5,  Jennifer Roth 6,  Matthew Rees 6,  Melissa Ronan 6,  Antonio Cuevas-Navarro 7,  Feng Hu 7,  Piro Lito 7 8,  David Santamaria 9,  Andrew J Aguirre 4 6 10 11,  Andrew M Waters 3 5 12 13,  Channing J Der 5 12,  Chiara Ambrogio 2,  Zhengping Wang 1,  Adrian L Gill 1,  Elena S Koltun 1,  Jacqueline A M Smith 14,  David Wildes 15,  Mallika Singh 16
Affiliations

Affiliations

  • 1 Revolution Medicines, Redwood City, CA, USA.
  • 2 Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
  • 3 Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 6 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 7 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • 9 Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
  • 10 Harvard Medical School, Boston, MA, USA.
  • 11 Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • 12 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 13 Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
  • 14 Revolution Medicines, Redwood City, CA, USA. jan@revmed.com.
  • 15 Revolution Medicines, Redwood City, CA, USA. pete@revmed.com.
  • 16 Revolution Medicines, Redwood City, CA, USA. msingh@revmed.com.
PMID: 38589574 DOI: 10.1038/s41586-024-07205-6
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).

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