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Updated: Jun 14, 2025

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RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade

Marie-Julie Nokin1,2, Alessia Mira3, Enrico Patrucco3

  • 1INSERM U1312, University of Bordeaux, IECB, Pessac, France.

Nature Communications
|August 30, 2024
PubMed

Insights

Targeting the KRAS G12C oncogene with inhibitors like sotorasib can lead to drug resistance. New strategies using KRAS G12C(ON) inhibitors may overcome resistance by targeting the active form of the oncogene.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Selective KRAS G12C inhibitors (sotorasib, adagrasib) are approved for advanced non-small cell lung cancer.
  • Drug resistance arises from acquired KRAS mutations and adaptive mechanisms increasing KRAS-GTP loading.

Purpose of the Study:

  • To investigate alternative therapeutic strategies to overcome resistance to KRAS G12C inhibitors.
  • To evaluate the potential of targeting the active GTP-bound (ON) state of KRAS G12C.

Main Methods:

  • Utilized the preclinical KRAS G12C(ON) inhibitor RMC-4998 (RM-029).
  • Assessed the efficacy of RMC-6291 (a clinical stage KRAS G12C(ON) inhibitor) alone and in combination with KRAS G12C(OFF) drugs.

Main Results:

  • Demonstrated that disease progression can occur via adaptive mechanisms and increased KRAS-GTP loading.
  • Provided proof-of-concept for KRAS G12C(ON) inhibitors as a strategy to circumvent resistance.

Conclusions:

  • Targeting the active KRAS G12C(ON) state offers a potential therapeutic approach.
  • Combination therapy with KRAS G12C(ON) and KRAS G12C(OFF) inhibitors may overcome resistance mechanisms.

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