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Updated: Jan 18, 2026

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Tumor suppressor genes and KRAS G12C inhibitor resistance in non-small cell lung cancer

Linsha Zhu1, Xiangbo Jia2, Lei Xu2

  • 1Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.

Iscience
|January 16, 2026
PubMed

Insights

KRAS G12C inhibitors offer new hope for cancer patients, but resistance is common. Tumor suppressor gene mutations are key drivers of this resistance in KRAS-driven non-small cell lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS G12C inhibitors have transformed cancer therapy, particularly for non-small cell lung cancer (NSCLC).
  • Therapeutic efficacy is often limited by primary and acquired resistance mechanisms.
  • Tumor suppressor gene (TSG) co-mutations are increasingly recognized as critical mediators of resistance in KRAS G12C-mutated cancers.

Purpose of the Study:

  • To review the diverse resistance mechanisms in KRAS G12C-mutated NSCLC.
  • To elucidate the role of tumor suppressor gene alterations in mediating resistance to KRAS G12C inhibitors.
  • To discuss preclinical models for studying resistance.

Main Methods:

  • Literature review of clinical and preclinical studies.
  • Analysis of emerging evidence on resistance mechanisms.
  • Focus on the interplay between KRAS mutations and TSG alterations.

Main Results:

  • Resistance to KRAS G12C inhibitors is heterogeneous and complex.
  • Co-mutations in TSGs are a significant driver of resistance in KRAS G12C-mutated NSCLC.
  • TSG alterations facilitate resistance through pathways including proliferation, metabolism, plasticity, and immune modulation.

Conclusions:

  • Understanding TSG alterations is crucial for overcoming resistance to KRAS G12C inhibitors.
  • Targeting these resistance pathways may improve therapeutic outcomes.
  • Further research using preclinical models is needed to advance the study of resistance mechanisms.
Keywords:
CancerGene networkTherapeutics

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