Neuroblastoma RAS viral oncogene homolog G12C (NRAS G12C)

Neuroblastoma RAS viral oncogene homolog G12C (NRAS G12C) is a specific oncogenic mutant of the NRAS protein, a member of the small GTPase family that functions as a molecular switch in intracellular signal transduction. Under normal physiological conditions, NRAS cycles between an active GTP-bound state and an inactive GDP-bound state to regulate critical cellular processes such as proliferation and survival via the MAPK and PI3K/AKT pathways [3, 12, 20]. The G12C mutation involves a substitution of glycine with cysteine at codon 12, which impairs GTP hydrolysis and leads to the protein remaining in a constitutively active state that drives tumor growth [3, 9, 10]. While NRAS mutations are most prevalent in melanoma, the G12C variant is a rarer but actionable driver found in colorectal, lung, and various other cancers [1, 3, 6]. Recent clinical advances have shown that covalent inhibitors originally designed for KRAS G12C, most notably sotorasib, can potently target the switch-II pocket of NRAS G12C to lock it in an inactive state [1, 2, 5]. Despite showing clinical activity, therapeutic challenges include bypass signaling through other RAS isoforms or upstream receptors, necessitating the exploration of combination therapies to achieve durable responses [6, 21, 22].

Other names

N-RasGTPase NRasNRAS proto-oncogene, GTPaseNeuroblastoma RAS viral oncogene homologNCMSALPS4CMNS

Covalent irreversible inhibition of the cysteine residue at position 12, locking the NRAS protein in its inactive GDP-bound state and preventing downstream oncogenic signaling.