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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
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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
Summary
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.
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