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Differential Response and Resistance to KRAS-Targeted Therapy

Zhaojin Liu1,2, Heinz-Josef Lenz1,2, Jian Yu1,2

  • 1Department of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, California, USA.

Molecular Carcinogenesis
|April 21, 2025
PubMed

Insights

KRAS G12C inhibitors offer new hope for cancer, but resistance is a major hurdle. This review explores resistance mechanisms and combination strategies to improve KRAS-targeted therapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • KRAS is a frequently mutated oncogene in epithelial cancers, particularly lung, colorectal, and pancreatic tumors.
  • KRAS G12C inhibitors (sotorasib, adagrasib) represent a breakthrough in targeted therapy for KRAS-mutated cancers.
  • Intrinsic and acquired resistance limit the efficacy of current KRAS G12C inhibitors.

Purpose of the Study:

  • To review mechanisms of intrinsic and acquired resistance to KRAS-targeted therapy.
  • To discuss resistance patterns in colorectal, lung, and pancreatic cancers.
  • To explore combination strategies to overcome resistance and enhance therapeutic outcomes.

Main Methods:

  • Review of recent clinical and preclinical studies.
  • Analysis of resistance mechanisms in various cancer types.
  • Synthesis of data on combination therapy approaches.

Main Results:

  • Many patients exhibit primary or acquired resistance to KRAS G12C inhibitors.
  • Colorectal cancer shows lower response rates and quicker resistance compared to non-small cell lung cancer.
  • Multiple resistance pathways necessitate novel therapeutic strategies.

Conclusions:

  • Overcoming resistance is critical for durable responses in KRAS-mutated cancers.
  • Combination therapies targeting resistance mechanisms hold promise for improving patient outcomes.
  • Further research is needed to optimize KRAS-targeted treatment regimens.
Keywords:
G12CKRASadagrasibcolorectal cancernon‐small cell lung cancersotorasib

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