Kirsten rat sarcoma viral oncogene homolog protein G12C mutant (KRAS G12C)

The **Kirsten rat sarcoma viral oncogene homolog protein G12C mutant**—commonly abbreviated as **KRAS G12C**—is a mutated form of the small GTPase enzyme K-Ras. This mutation involves substitution of glycine with cysteine at position 12. The normal K-Ras protein acts as a molecular switch regulating cell growth and division by cycling between active (GTP-bound) and inactive (GDP-bound) states. Mutations such as G12C impair intrinsic GTP hydrolysis activity, resulting in constitutive activation that drives uncontrolled cellular proliferation—a hallmark of many cancers including lung adenocarcinoma, colorectal cancer, and pancreatic ductal adenocarcinoma. KRAS has historically been considered "undruggable" due to its high affinity for endogenous nucleotides and lack of suitable binding pockets; however, recent advances have led to development of covalent inhibitors that specifically target the unique cysteine residue introduced by this mutation without affecting wild-type KRAS. These inhibitors allosterically disrupt nucleotide preference and effector interactions critical for downstream signaling.

Other names

K-Ras G12CKRAS(G12C)K-Ras glycine 12 to cysteine mutantKRAS p.Gly12CysKirsten rat sarcoma viral oncogene homolog (KRAS)

Drugs targeting KRAS G12C act as covalent inhibitors that irreversibly bind to the unique cysteine residue at position 12. This binding locks the protein in its inactive GDP-bound state, preventing downstream signaling through pathways such as MAPK/ERK and PI3K/AKT.