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RAS-GTP Inhibition Overcomes Acquired Resistance to KRASG12C Inhibitors Mediated by Oncogenic and Wild-Type RAS

Hitendra S Solanki1, Harshit Shah2, Denis Imbody1

  • 1Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Cancer Research
|October 30, 2025
PubMed

Insights

KRASG12C inhibitors show initial efficacy but resistance develops. New strategies targeting both inactive and active RAS states, including dual inhibition and multi-selective inhibitors, can overcome resistance mechanisms in KRAS-mutant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRASG12C inhibitors targeting the inactive GDP-bound state are effective but face transient responses due to resistance.
  • RAS(ON) G12C-selective inhibitors targeting the active GTP-bound state, like elironrasib, are emerging as new therapeutic options.

Purpose of the Study:

  • To investigate resistance mechanisms to both KRASG12C(OFF) and RAS(ON) G12C-selective inhibitors.
  • To identify therapeutic strategies to overcome acquired resistance in KRAS-mutant cancers.

Main Methods:

  • Generation of resistant cell lines and patient-derived xenograft models.
  • Multi-omics analysis including phosphoproteomics, whole exome sequencing, and RNA-sequencing.
  • Functional validation using small molecule and CRISPR screens, and RAS(ON) inhibitors.

Main Results:

  • Two models reactivated RAS signaling via KRASG12C amplification or NRASG13R mutation, responding to dual RAS(ON) G12C-selective and multi-selective inhibition (RMC-4998, RMC-7977).
  • Two models developed resistance via increased receptor tyrosine kinase activity, showing sensitivity to RAS-GTP inhibition by RMC-7977.
  • One model exhibited epithelial-mesenchymal transition and reliance on cell cycle kinases and DNA damage response proteins.

Conclusions:

  • Identified diverse resistance mechanisms to KRASG12C inhibitors, mirroring clinical observations.
  • Demonstrated that RAS(ON) multi-selective inhibitors can overcome a significant subset of resistance, as monotherapy or in combination.

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