KRAS proto-oncogene, GTPase (G12C mutation) (KRAS G12C)

KRAS (Kirsten rat sarcoma viral oncogene homolog) is a small GTPase that functions as a molecular switch, cycling between an active GTP-bound state and an inactive GDP-bound state to regulate critical cellular signaling pathways such as MAPK/ERK and PI3K/AKT/mTOR [UniProt P01116]. The G12C mutation involves a single-nucleotide substitution where glycine is replaced by cysteine at codon 12, which impairs intrinsic GTPase activity and prevents GAP-mediated hydrolysis, effectively trapping KRAS in a constitutively active state that drives malignant transformation [PubMed: 31653892]. This specific mutation is highly prevalent in certain cancers, occurring in approximately 13% of non-small cell lung cancers (NSCLC) and 1-3% of colorectal and other solid tumors [National Cancer Institute]. Historically considered 'undruggable' due to its lack of deep binding pockets, the discovery of a targetable 'Switch II' pocket enabled the development of covalent inhibitors that specifically bind the mutant cysteine residue when the protein is in its inactive GDP-bound state [PubMed: 24256730]. Targeted therapies like sotorasib and adagrasib have successfully demonstrated the ability to inhibit tumor growth by blocking this aberrant signaling. However, clinical management remains challenged by the emergence of acquired resistance, often occurring through secondary mutations in the KRAS binding pocket or the activation of bypass signaling pathways [PubMed: 34161702].

Other names

Kirsten rat sarcoma viral oncogene homologp21 rasRASK2K-Ras 2c-K-rasGTPase KRas

Covalent inhibition of the mutant KRAS G12C protein by binding to the cryptic Switch II pocket (S-IIP) specifically in its inactive, GDP-bound state, thereby locking the protein in an inactive conformation and preventing downstream oncogenic signaling.