KRAS G12 refers to a group of specific mutations in the KRAS gene at codon 12, where the glycine (G) residue is substituted by another amino acid.
These mutations are common oncogenic drivers in various cancers, particularly non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).
The most prevalent KRAS G12 mutations include: • G12C (glycine to cysteine) • G12D (glycine to aspartic acid) • G12V (glycine to valine) • G12A (glycine to alanine)
KRAS G12C is notable for the presence of specific inhibitors like sotorasib and adagrasib showing clinical efficacy.
These inhibitors covalently bind to the cysteine residue at position 12, locking KRAS in its inactive GDP-bound state and inhibiting downstream signaling pathways.
KRAS G12D, on the other hand, is the most prevalent KRAS mutation across various carcinomas and is associated with different clinical and biological characteristics compared to G12C.
KRAS G12D is often found in patients with a lower smoking history and is associated with a lower tumor mutation burden and PD-L1 expression.
KRAS G12V has been associated with a worse prognosis in NSCLC compared to other KRAS mutations.