KRAS

About KRAS

KRAS on chromosome 12p12.1 encodes a small GTPase in the RAS MAPK signaling pathway that cycles between an active GTP bound state and an inactive GDP bound state. It is one of the most frequently mutated oncogenes in human cancer, with mutations in the great majority of pancreatic cancers and in a large share of colorectal cancers and lung adenocarcinomas. Most mutations occur at codons 12, 13, or 61 and impair GTP hydrolysis, locking KRAS in the active state and causing constitutive signaling. The name comes from the Kirsten rat sarcoma virus, in which the oncogene was first identified. For decades KRAS was considered undruggable because the protein lacks obvious drug binding pockets. Covalent inhibitors targeting the G12C mutation, which is especially common in lung adenocarcinoma of smokers, bind a pocket under the switch II region, and sotorasib was approved in 2021, followed by adagrasib in 2022. Inhibitors of other variants, such as G12D, and pan RAS inhibitors are in development. KRAS mutant colorectal cancers do not respond to anti EGFR antibodies such as cetuximab and panitumumab, so KRAS testing is routinely used to guide treatment. Germline KRAS variants cause rare RASopathies such as Noonan syndrome.