What KRAS mutations occur in lung cancer, and what is the difference between KRAS G12C and KRAS G12A?

2026-09-15

In non-small cell lung cancer (NSCLC), KRAS is one of the most common oncogenic driver genes, which most frequently involves mutations in codon 12. The most common variant is KRAS G12C; additionally, G12V, G12D, G12A, more rarely G12F, and alterations affecting other codons (such as G13 or Q61) also occur. The fundamental biochemical and therapeutic difference between KRAS G12C and KRAS G12A stems from the nature of the amino acid substitution: in the case of the G12C mutation, the glycine at position 12 is replaced by cysteine, to whose nucleophilic thiol group specific, covalent KRAS G12C inhibitors (such as sotorasib, adagrasib, or fulzerasib) can targetedly bind in the inactive GDP-bound form. In contrast, in the KRAS G12A mutation, glycine is replaced by alanine; alanine lacks this reactive cysteine side chain capable of forming a covalent bond, and therefore the approved G12C-specific covalent inhibitors are ineffective against it, necessitating the investigation of other approaches (such as pan-RAS/pan-KRAS inhibitors or combination therapies) for the treatment of such tumours.\n\nIn the field of clinical trials, for targeting non-G12C variants such as KRAS G12A, G12D, or G12V, broader-spectrum agents targeting the RAS/MAPK pathway are being investigated, such as in the Phase 1/2 trial of S241656 (NCT05786924) in metastatic or recurrent lung cancer.\n\nIn KRAS G12C-mutant lung cancer, the development of resistance represents a frequent obstacle during the use of targeted inhibitors (such as sotorasib or adagrasib), which may be driven by compensatory reactivation of other pathways or concurrent genetic alterations.

References

  1. Adagrasib in Non‑Small‑Cell Lung Cancer Harboring a KRAS(G12C) Mutation doi:10.1056/NEJMoa2204619
  2. Tumor suppressor genes and KRAS G12C inhibitor resistance in non-small cell lung cancer doi:10.1016/j.isci.2025.114429
  3. Cetuximab co‑treatment with KRAS G12C inhibitors fulzerasib and sotorasib in human KRAS G12C non‑small cell lung cancer cells nct:NCT05756153
  4. Advances in the treatment of KRAS<sup>G12C</sup> mutant non-small cell lung cancer. PMID 40172157
  5. Kristen rat sarcoma virus (KRAS) G12F-positive non-small cell lung cancer mimicking KRAS G12C positivity: A case report. PMID 38010032
  6. Phase 1/2 Trial of S241656 in Selected RAS/MAPK Mutation- Positive Malignancies NCT05786924

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