Neuroblastoma RAS viral oncogene homolog (NRAS) G12R (NRAS G12R)

Neuroblastoma RAS viral oncogene homolog (NRAS) G12R is a specific oncogenic missense mutation where the glycine at position 12 is replaced by arginine. This alteration impairs the protein's intrinsic GTPase activity and prevents GTPase-activating proteins (GAPs) from effectively catalyzing the hydrolysis of GTP to GDP, thereby trapping NRAS in a constitutively active state [1, 3, 11]. In its active conformation, NRAS G12R continuously stimulates downstream signaling cascades, primarily the MAPK/ERK and PI3K/AKT pathways, which drive malignant transformation, uncontrolled cell proliferation, and enhanced survival [14, 17]. This mutation is frequently identified in hematologic malignancies such as acute myeloid leukemia (AML) and is also found in solid tumors like melanoma and colorectal cancer [1, 15]. Clinically, NRAS G12R serves as a critical predictive biomarker in colorectal cancer, where its presence indicates a lack of response to anti-EGFR monoclonal antibody therapies like cetuximab [1, 3, 9]. While direct, allele-specific inhibitors for the G12R variant are currently under preclinical investigation using novel covalent chemistries targeting the arginine residue, current clinical strategies rely on downstream pathway inhibition or emerging pan-RAS inhibitors that target multiple G12-mutated variants [11, 16, 17].

Other names

Neuroblastoma RAS viral oncogene homolog p.Gly12ArgNRAS p.G12RTransforming protein N-Ras G12RNRAS proto-oncogene, GTPase G12R mutationN-Ras G12R

Inhibition of downstream MAPK/ERK pathway signaling via MEK or ERK inhibitors, blockade of RAS-SOS1 interaction to prevent nucleotide exchange, or direct multi-allele RAS inhibition of the active (GTP-bound) state to suppress oncogenic drive.