Activated Kirsten rat sarcoma virus oncogene homolog (KRAS), Neuroblastoma RAS viral oncogene homolog (NRAS), and Harvey rat sarcoma virus oncogene homolog (HRAS) (RAS)

RAS proteins, including the isoforms KRAS (Kirsten rat sarcoma virus oncogene homolog), NRAS (Neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey rat sarcoma virus oncogene homolog), are small GTPases that function as critical molecular switches in cellular signal transduction (UniProt P01116, P01112, P01111). They cycle between an inactive GDP-bound state and an active GTP-bound state, regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) (PubMed: 33408225). When active, RAS proteins recruit and activate downstream effector pathways, such as the MAPK/ERK and PI3K/AKT pathways, which govern essential processes like cell proliferation, differentiation, and survival (NIH/NCI). Mutations in RAS genes, which impair their intrinsic GTPase activity or GAP-mediated GTP hydrolysis, result in the proteins being constitutively locked in the "on" state, driving oncogenesis (PubMed: 31911637). These mutations are prevalent in approximately 30% of all human cancers, with KRAS being the most frequently mutated isoform in pancreatic, colorectal, and lung cancers (Nature Reviews Cancer, 2020). While long considered "undruggable" due to their high affinity for GTP and lack of deep binding pockets, recent therapeutic advances have introduced covalent inhibitors targeting specific mutants like KRAS G12C and "RAS-multi" inhibitors that target the active state of multiple RAS isoforms (PubMed: 35618837).

Other names

p21 rasTransforming protein p21GTP-binding proteinK-RasN-RasH-RasRAS oncogeneGTP-bound RAS

Direct inhibition of the active GTP-bound state (ON-state) or covalent modification of specific mutant residues (e.g., G12C) to lock the protein in an inactive GDP-bound state (OFF-state), thereby preventing interaction with downstream effectors like RAF and PI3K.