Kirsten rat sarcoma virus proto-oncogene GTPase (KRAS) (KRAS)

Kirsten rat sarcoma virus proto-oncogene GTPase (KRAS) is a small GTPase that functions as a critical molecular switch in cellular signaling pathways, including the MAPK/ERK and PI3K/AKT/mTOR pathways (UniProt P01116). In its normal state, KRAS cycles between an active GTP-bound form and an inactive GDP-bound form to regulate cell growth, differentiation, and survival (PubMed: 31666701). Mutations in the KRAS gene, particularly at codons 12, 13, and 61, impair the protein's intrinsic GTPase activity and its response to GTPase-activating proteins, resulting in a constitutively active state that drives oncogenesis (NIH: Gene ID 3845). These mutations are highly prevalent in some of the most aggressive malignancies, including pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer (PubMed: 34010246). While long considered "undruggable" due to its high affinity for GTP and lack of accessible binding pockets, recent therapeutic advances have successfully targeted specific mutants like KRAS G12C (FDA: Lumakras). Covalent inhibitors such as sotorasib and adagrasib bind to a cryptic pocket in the inactive GDP-bound state, effectively trapping the protein and inhibiting downstream signaling (PubMed: 31666701). Current research is expanding to target other common mutations, such as G12D and G12V, as well as developing pan-KRAS inhibitors to overcome diverse oncogenic drivers (ClinicalTrials.gov).

Other names

KRAS2RASK2KI-RASC-K-RASK-RASKirsten rat sarcoma viral oncogene homologMutated KRAS

Covalent inhibition of the KRAS G12C mutant protein by binding to the switch-II pocket, locking the protein in its inactive GDP-bound state and preventing downstream oncogenic signaling (PubMed: 31666701).