Kirsten rat sarcoma virus oncogene homolog (KRAS) (KRAS)

Kirsten rat sarcoma virus oncogene homolog (KRAS) is a small GTPase that functions as a critical molecular switch in the Ras/MAPK and PI3K/AKT signaling 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: 33408150). Mutations in the KRAS gene, most commonly at codons 12, 13, or 61, result in a protein that is constitutively active, driving uncontrolled cell growth and oncogenesis (NIH: National Cancer Institute). These mutations are found in approximately 25% of all human tumors, with particularly high frequencies in pancreatic (90%), colorectal (40%), and lung (30%) cancers (PubMed: 31484074). While long considered "undruggable" due to its smooth surface and high affinity for GTP, the discovery of a cryptic pocket in the G12C mutant led to the development of covalent inhibitors like sotorasib and adagrasib (PubChem: CID 137530429). These therapies specifically target the inactive state of the KRAS G12C protein, though clinical challenges remain, including the emergence of acquired resistance and the need for inhibitors targeting other common variants like G12D and G12V (PubMed: 34133854).

Other names

KRAS2RASK2c-K-rasK-Ras 2Ki-RasGTPase KRas

Covalent inhibition of the KRAS G12C mutant protein, locking it in the inactive GDP-bound state to prevent downstream signaling (PubMed: 31666304).