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Therapeutic strategies for KRAS G12C-mutant non-small cell lung cancer: from bench to bedside and beyond

Renjie Huang1,2,3, Xian Gong1,3, Jianting Du1,3

  • 1Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.

Frontiers in Pharmacology
|February 11, 2026
PubMed

Insights

KRAS G12C inhibitors show promise for non-small cell lung cancer (NSCLC). However, resistance limits effectiveness, necessitating combination strategies and novel therapies for improved outcomes in KRAS-mutant NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS mutations are prevalent in non-small cell lung cancer (NSCLC), especially lung adenocarcinoma (15-25%).
  • KRAS was historically considered undruggable, but selective KRAS G12C inhibitors (sotorasib, adagrasib) are now available.
  • These targeted therapies show clinical efficacy but face resistance, limiting long-term patient benefit.

Purpose of the Study:

  • To comprehensively review KRAS G12C structural biology and its role in oncogenic signaling.
  • To analyze challenges in KRAS G12C targeted therapy, including resistance mechanisms.
  • To explore future therapeutic strategies, including combination regimens and precision medicine.

Main Methods:

  • Literature review and analysis of existing studies on KRAS G12C inhibitors.
  • Examination of structural biology data related to KRAS G12C.
  • Discussion of clinical trial outcomes and resistance mechanisms.

Main Results:

  • KRAS G12C inhibitors offer a new therapeutic avenue for NSCLC patients.
  • Intrinsic and acquired resistance mechanisms frequently emerge, reducing monotherapy efficacy.
  • Combination strategies and novel inhibitors are being investigated to overcome resistance.

Conclusions:

  • Targeted therapy for KRAS G12C-mutant NSCLC requires strategies to overcome resistance.
  • Future research should focus on combination regimens and novel inhibitors.
  • Precision medicine approaches hold promise for optimizing treatment outcomes.
Keywords:
KRAS G12Ccombination strategiesdrug resistancenon-small cell lung cancer (NSCLC)targeted therapy

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