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[Breakthroughs in KRAS G12C-mutant advanced colorectal cancer: from mechanisms to clinical practice]
1Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Abstract:
KRAS mutations are major oncogenic drivers in colorectal cancer (CRC), occurring in 35%-49% of cases; of which 3%-4% involve the KRAS G12C subtypes, characterized by a glycine-to-cysteine substitution at codon 12. This variant is associated with poor treatment response and reduced overall survival. Recent phase I/II trials of KRAS G12C inhibitors have shown promising results, and the phase III CodeBreaK 300 study confirmed that sotorasib combined with panitumumab significantly improved efficacy compared with standard treatment, establishing a new therapeutic option for KRAS G12C-mutant metastatic CRC. However, drug resistance inevitably develops, driven by mechanisms such as feedback activation of signaling pathways, secondary mutations, and epithelial-mesenchymal transition. Strategies under investigation include targeting alternative signaling pathways, developing next-generation inhibitors and specific degraders, and exploring multi-mechanism or multi-target combination strategies. This review systematically outlines the development of KRAS G12C inhibitors in mCRC, summarizes resistance mechanisms, and discusses emerging combination regimens, aiming to provide a theoretical basis and future directions for treatment optimization.
Insights
KRAS G12C inhibitors show promise for metastatic colorectal cancer (CRC). Combination therapies are being explored to overcome drug resistance and improve patient survival in KRAS G12C-mutant CRC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- KRAS mutations drive 35%-49% of colorectal cancer (CRC) cases.
- KRAS G12C subtype (3%-4% of CRC) is linked to poor treatment outcomes.
- KRAS G12C inhibitors offer a new therapeutic avenue for metastatic CRC.
Purpose of the Study:
- To review KRAS G12C inhibitor development in metastatic CRC.
- To summarize resistance mechanisms against KRAS G12C inhibitors.
- To discuss emerging combination strategies for treatment optimization.
Main Methods:
- Systematic review of KRAS G12C inhibitor development.
- Analysis of resistance mechanisms including pathway activation and mutations.
- Evaluation of current and future combination regimens.
Main Results:
- KRAS G12C inhibitors, like sotorasib, demonstrate efficacy in metastatic CRC.
- Drug resistance arises from diverse mechanisms, including feedback signaling and secondary mutations.
- Combination strategies are crucial for overcoming resistance and enhancing treatment efficacy.
Conclusions:
- KRAS G12C inhibitors represent a significant advancement in metastatic CRC treatment.
- Understanding and overcoming resistance mechanisms are critical for long-term patient benefit.
- Further research into combination therapies will optimize treatment strategies for KRAS G12C-mutant CRC.
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