G12C

G12C refers to a specific point mutation in the KRAS gene, where glycine at codon 12 is replaced by cysteine (p.G12C). This alteration produces an oncogenic KRAS protein that is constitutively active and drives signaling through the MAPK and PI3K pathways, contributing to the growth and survival of several cancers, most notably non-small cell lung cancer (NSCLC). Among KRAS mutations, G12C is the most common in NSCLC.

For many years KRAS was considered undruggable due to the protein’s high affinity for GTP/GDP and a lack of deep drug-binding pockets. The G12C substitution creates a unique cysteine that covalent inhibitors can target. Drugs such as sotorasib and adagrasib covalently modify Cys12 in the inactive GDP-bound state within a switch II pocket, locking KRAS G12C in an inactive conformation and attenuating downstream signaling.

Clinical development led to regulatory approvals: sotorasib (Lumakras) received FDA approval in 2021 for KRAS G12C-mutant NSCLC after at least one prior systemic therapy, and adagrasib (Krazati) followed with an approval in 2022. Both agents are being investigated in other tumor types and in combination regimens, including combinations with EGFR inhibitors, SHP2 inhibitors, MEK inhibitors, or immunotherapies, in an effort to broaden efficacy and overcome resistance.

Limitations include the emergence of resistance, which can arise through secondary KRAS mutations, activation of alternative signaling pathways, or histologic transformation. Ongoing research focuses on combination strategies and next-generation inhibitors to extend benefit and address resistant disease. G12C remains a major focus of targeted therapy for KRAS-driven cancers.