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 G12 D variant occurs in 5% of patients with non-small cell lung cancer and is the most common substitution variant in pancreatic duct adenocarcinoma, occurring in 40% of the patients.
Setidegrasib a KRAS G 12 D – targeted protein degrader with anti-turmoric activity and low incidence of treatment discontinuation due to adverse events in patients previously treated KRAS 12 D mutated NSCLC or pancreatic ductal adenocarcinoma.
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.
KRAS mutations occur in nearly 40% of patients with lung cancer, and among patients with colorectal cancer, as many as 5% have a KRAS G12C mutation.
KRASG 12 C inhibitors include sotorasib and adagrasib.
G12C mutation is more common in women.
In colorectal cancer KRAS G12 mutations are associated with a poor prognosis than other G 12 mutations, whereas KRAS G12 R has a more favorable prognosis.
KRAS mutations are associated with resistance to anti EGFR therapies limiting affecting this of targeted treatments for patients with KRAS mutations.