From “Undruggable” to Tractable: Therapeutic Advances Targeting KRAS G12C-Mutant Cancers and Emerging Resistance Mechanisms

This review explains the evolution of Kirsten rat sarcoma viral oncogene homolog glycine to cysteine mutation at codon 12 ( KRAS G12CG12C) from an “undruggable” target to a manageable oncogenic driver in non-small cell lung cancer (NSCLC). While first-generation inhibitors have significantly improved patient care, the emergence of complex resistance mechanisms necessitates a shift toward precision-driven combination therapies and advanced computational drug discovery. The KRAS G12C mutation is a primary driver in approximately 8.9% of NSCLC patients, particularly smokers. The development of covalent inhibitors, which lock the mutant protein in its inactive state, has transformed treatment for these patients. The Food and Drug Administration (FDA)-approved inhibitors AMG510 (sotorasib) and MRTX-849 (adagrasib) achieve response rates of 30%–43%. Patients typically experience a median progression-free survival of 6.5 months, although the duration of response is often limited to 8–11 months due to resistance. New inhibitors, such as grasorasib, glecirasib, and fulzerasib have recently gained regulatory momentum in China, reporting objective response rates (ORRs) of up to 47.9%. Co-mutational context heavily influences clinical outcomes, which determines whether a tumor is immunologically “hot” or “cold”. Tumor protein p53 (TP53) co-mutations often result in an “inflamed” environment, correlating with superior responses to immune checkpoint inhibitors. Serine/threonine kinase 11 (STK11) and kelch-like ECH-associated protein 1 (KEAP1) co-mutations typically promote resistance to both immunotherapy and monotherapy, and require multimodal treatment approaches. Tumors eventually evade treatment through secondary mutations or by bypassing signaling pathways such as mesenchymal-epithelial transition tyrosine kinase (MET) or epidermal growth factor receptor (EGFR). To improve disease control, the field is moving towards next-generation inhibitors and enhanced monitoring. next-generation compound development is focused on dual-state and pan- RAS inhibitors that engage the protein in both its active and inactive forms. Computational tools are being used to accelerate scaffold discovery and predict how mutations might evade new drugs. Real-time monitoring utilizing ctDNA-based liquid biopsies allows for the detection of minimal residual disease and “molecular lead time” to anticipate resistance before it is visible on scans. Standardizing biomarker scoring and ensuring global access to these targeted therapies are essential for equitable care. By integrating structure-based design with personalized combination strategies, the goal is to transform KRAS G12C from a transiently targetable mutation into a chronically manageable condition. • Kirsten rat sarcoma viral oncogene homolog glycine to cysteine mutation at codon 12 ( KRAS G12C) as target: Key oncogenic driver in non-small cell lung cancer (NSCLC) (∼9%), rendered druggable via cysteine-targeted covalent inhibitors. • Current drugs: Sotorasib and adagrasib show efficacy but face resistance; newer Chinese National Medical Products Administration drugs report improved outcomes. • Next-generation development: Structure-based modelling, molecular dynamics, and ML accelerate potent, resistance-overcoming inhibitors. • Precision medicine: Circulating tumor deoxyribonucleic acid (ctDNA) monitoring and biomarker-guided strategies support durable and globally accessible KRAS G12C therapy.