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

Source: https://onco.cc/key-papers/paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024/  
OnCo record `paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The 2024 Nature paper describing the chemistry behind daraxonrasib: a reversible drug that clamps the active form of every RAS protein, mutant or normal, and shrank tumours across RAS-driven models.

## Summary

Holderfield and colleagues at Revolution Medicines describe RMC-7977, a reversible tri-complex RAS inhibitor with broad-spectrum activity for the active (GTP-bound) state of mutant and wild-type KRAS, NRAS and HRAS, a RAS(ON) multi-selective inhibitor. Preclinically it showed potent activity against RAS-addicted tumours of various genotypes, particularly models with KRAS codon 12 mutations, led to tumour regression, was well tolerated in diverse models and inhibited KRAS G12C models that had become resistant to G12C inhibitors through restored RAS pathway signalling. The paper notes that KRAS G12C accounts for only around 15 percent of KRAS-mutant cancers and that no inhibitor was approved for the rest, and that the related compound RMC-6236 (daraxonrasib) was in clinical evaluation (NCT05379985).

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: pancreatic-evidence
- Journal: Nature
- Year: 2024
- DOI: 10.1038/s41586-024-07205-6
- Authors: Holderfield M, Lee BJ, Jiang J, et al.
- Findings: RMC-7977 inhibits GTP-bound mutant and wild-type KRAS, NRAS and HRAS.; Regression in RAS-addicted models, strongest in KRAS codon 12 mutants, with tolerability.; Activity in G12C models resistant to G12C inhibitors.; KRAS G12C is around 15 percent of KRAS-mutant cancers; daraxonrasib (RMC-6236) was already in trials.
- What it means: The mechanism that let one drug address G12D, G12V and G12R together, which is why the RASolute 302 trial could enrol unselected pancreatic cancer and nearly double survival.
- Caveats: Preclinical; the human data are in the RASolute 302 paper.; Inhibiting wild-type RAS raises the question of on-target toxicity (rash, stomatitis) that the trials measure.

## Sources

- Nature 2024: https://doi.org/10.1038/s41586-024-07205-6
- PubMed: https://pubmed.ncbi.nlm.nih.gov/38589574/

## Connected records

- roadmaps: [KRAS roadmap: undruggable → G12C → pan-RAS](https://onco.cc/roadmaps/kras-roadmap/), [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/)
- key papers: [Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer](https://onco.cc/key-papers/paper-daraxonrasib-pancreatic-n-engl-j-med-2026/)
- cancers: [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/)
- targets: [KRAS](https://onco.cc/targets/kras/)
- drugs: [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/)
- companies: [Revolution Medicines](https://onco.cc/companies/revolution-medicines/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- trials: [RASolute 302](https://onco.cc/trials/rasolute-302/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- journals: [Nature](https://onco.cc/journals/nature/)
- ideas: [RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression](https://onco.cc/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/)

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