GTPase KRas (KRAS) (KRAS)

GTPase KRas (KRAS) is a small GTPase that functions as a critical molecular switch in cellular signaling pathways, including the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR pathways. It cycles between an active GTP-bound state and an inactive GDP-bound state, regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Under normal physiological conditions, KRAS regulates essential processes such as cell proliferation, differentiation, and survival (UniProt P01116). However, point mutations in the KRAS gene—most frequently at codons 12, 13, and 61—impair its intrinsic GTPase activity and render it insensitive to GAPs, leading to constitutive activation. This persistent signaling drives the development and progression of several aggressive cancers, most notably pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer (PubMed: 33408234). For decades, KRAS was deemed "undruggable" due to its smooth surface and picomolar affinity for GTP, but the discovery of a cryptic pocket in the G12C mutant allowed for the development of covalent inhibitors like sotorasib and adagrasib (PubMed: 24107992). Current therapeutic strategies focus on allele-specific inhibitors, pan-KRAS inhibitors, and targeting downstream effectors or upstream regulators like SOS1.

Other names

Kirsten rat sarcoma virus oncogene homologKRAS2RASK2KI-RASC-K-RASK-RAS4AK-RAS4B

Allele-specific covalent inhibition of the KRAS G12C mutant protein, locking it in the inactive GDP-bound state to prevent downstream signaling, as well as emerging pan-KRAS and G12D-specific inhibition strategies.