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Updated: Aug 11, 2026
09:29
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
[Therapeutic Strategies Targeting the KRAS G12C Mutation-Current Landscape and Future Directions]
Shinji Nakamichi1, Kaoru Kubota
1Dept. of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School.
Gan to Kagaku Ryoho. Cancer & Chemotherapy
|August 4, 2026
Summary
KRAS G12C inhibitors show promise for non-small cell lung cancer (NSCLC) but face resistance and toxicity. Next-generation drugs and combination therapies aim to improve outcomes for patients with KRAS-mutated NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- KRAS G12C is a key target in non-small cell lung cancer (NSCLC).
- Covalent inhibitors targeting KRAS G12C have made this oncogene actionable.
- First-generation inhibitors show activity but are limited by resistance and toxicity.
Purpose of the Study:
- To review the therapeutic landscape of KRAS G12C inhibitors in NSCLC.
- To discuss resistance mechanisms and emerging treatment strategies.
- To highlight the potential of next-generation inhibitors and combination therapies.
Main Methods:
- Review of clinical trial data and scientific literature.
- Analysis of resistance mechanisms and toxicity profiles.
- Exploration of novel therapeutic approaches, including RAS (ON) inhibitors.
Main Results:
- First-generation KRAS G12C inhibitors (sotorasib, adagrasib) have clinical activity but limited durability.
- Resistance arises from secondary KRAS alterations, bypass pathways, and MAPK reactivation.
- Hepatotoxicity is a concern, especially with prior immune checkpoint inhibitor use.
- Next-generation inhibitors (divarasib, glecirasib, olomorasib) show potential for improved efficacy and tolerability.
- Combination strategies (with ICI, SHP2, SOS1, MEK inhibitors) are under investigation.
- RAS (ON) inhibitors (daraxonrasib) represent a new therapeutic paradigm.
Conclusions:
- Optimal treatment selection for KRAS G12C NSCLC requires considering molecular heterogeneity, resistance, and toxicity.
- Next-generation inhibitors and combination therapies hold promise for enhancing response depth and durability.
- Patient-centered shared decision-making is crucial in evolving treatment landscape.
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