Kirsten rat sarcoma viral oncogene homolog (KRAS) G12R mutant protein (KRAS G12R)

The KRAS G12R mutation refers to a specific alteration in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, where glycine at position 12 is replaced by arginine. This mutation occurs within the P-loop region of the catalytic domain and results in constitutive activation of the KRAS protein, a small enzyme that functions as a molecular switch regulating cell growth and division through pathways such as MAPK. The G12R variant is particularly prevalent in pancreatic ductal adenocarcinoma—found in approximately 17% of cases—and also appears less frequently in other cancers like lung and colorectal cancer[1][2][3]. Mutant KRAS proteins are key drivers ("driver mutations") initiating malignant transformation by promoting uncontrolled cellular proliferation. The "always-on" state caused by this mutation disconnects normal regulatory signals from downstream effectors, leading to tumorigenesis[1]. While direct pharmacological targeting has historically been challenging due to structural features that limit drug binding, recent advances have enabled development of experimental covalent inhibitors that selectively bind mutated residues such as arginine at position 12. These agents inhibit nucleotide exchange activity critical for signaling function but remain investigational with no approved therapies specifically for this variant yet[2]. The presence or absence of specific KRAS mutations—including G12R—serves both prognostic purposes and guides enrollment into clinical trials evaluating targeted therapies. However, therapeutic challenges persist due to limited druggability and potential resistance mechanisms inherent to RAS-driven cancers[1][4].

Other names

KRAS p.G12RK-Ras(G12R)KRAS glycine 12 to arginine mutationKRAS G12R mutant

Covalent modification and inhibition of nucleotide exchange activity by small molecules binding to the Switch II pocket[2]