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

Kirsten rat sarcoma virus proto-oncogene (KRAS) is a small GTPase that functions as a critical molecular switch in intracellular signaling pathways, including the MAPK/ERK and PI3K/AKT cascades (UniProt: P01116). It cycles between an active GTP-bound state and an inactive GDP-bound state to regulate fundamental cellular processes such as proliferation, differentiation, and survival (PubMed: 33479115). Mutations in the KRAS gene, most commonly occurring at codons 12, 13, or 61, impair the protein's intrinsic GTPase activity and its responsiveness to GTPase-activating proteins (GAPs), resulting in a constitutively active state that drives oncogenesis (PubMed: 34108715). KRAS mutations are among the most frequent drivers in human cancers, particularly in pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer (PubMed: 31911631). While long considered undruggable due to its high affinity for GTP and lack of traditional small-molecule binding pockets, the discovery of a cryptic switch II pocket has enabled the development of allele-specific inhibitors (PubMed: 24256730). Drugs such as sotorasib and adagrasib covalently bind to the cysteine residue in the KRAS G12C mutant, trapping the protein in its inactive GDP-bound conformation (FDA: Lumakras, Krazati). Current therapeutic research is expanding to target other common variants like G12D and G12V, as well as developing pan-RAS inhibitors that target multiple isoforms (PubMed: 37224613). Despite clinical success, challenges remain, including the development of acquired resistance through secondary mutations or the activation of bypass signaling pathways (PubMed: 34161723).

Other names

KRAS2RASK2KI-RASc-K-rasK-rasKirsten rat sarcoma 2 viral oncogene homologv-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

Allele-specific covalent inhibition of the inactive GDP-bound state (e.g., G12C inhibitors), non-covalent inhibition of active or inactive states, and disruption of SOS1-mediated nucleotide exchange.