Drug repurposing in KRAS G12C-mutant NSCLC: a focus on resistance mechanisms and clinical strategies

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• KRAS G12C-mutant non-small cell lung cancer (NSCLC) was historically difficult to treat but is now a targetable cancer with approved therapies like sotorasib and adagrasib.
• Despite progress, acquired resistance limits the durability of responses to KRAS G12C inhibitors.
• Understanding resistance mechanisms is crucial for developing effective combination strategies.

Purpose of the Study:

• To review the current understanding of KRAS G12C biology and resistance mechanisms in NSCLC.
• To integrate updated clinical data and future inhibitor pipelines.
• To propose a drug repurposing framework for combination therapies targeting KRAS G12C resistance.

Main Methods:

• Literature review of KRAS G12C biology, clinical trial data, and next-generation inhibitors.
• Analysis of resistance mechanisms and identification of FDA-approved agents for repurposing.
• Highlighting translational platforms such as patient-derived 3D models, multi-omics, and ctDNA monitoring.

Main Results:

• KRAS G12C inhibitors have transformed NSCLC treatment, but adaptive resistance is a significant challenge.
• Multiple resistance pathways have been identified, creating a vulnerability map for therapeutic intervention.
• A framework is presented to match resistance mechanisms with available drugs for combination trials.

Conclusions:

• Repurposing approved agents offers a viable strategy to overcome KRAS G12C inhibitor resistance.
• Integrated translational approaches combining mechanistic insights and clinical innovation are essential.
• This strategy holds promise for improving precision therapy and patient outcomes in KRAS-driven NSCLC.