Kirsten rat sarcoma viral oncogene homolog GTPase G12S mutant protein (KRAS G12S)

The **KRAS G12S mutant protein** is a variant of the Kirsten rat sarcoma viral oncogene homolog (KRAS), in which glycine at position 12 is replaced by serine. This mutation impairs the GTPase activity of KRAS, rendering the protein constitutively active, thereby driving continuous cell growth and proliferation, which are hallmarks of many cancers—including colorectal adenocarcinoma and non-small cell lung cancer[1][2][4][5]. The G12S mutation causes subtle but significant changes in the conformational dynamics of the protein, particularly in the effector binding regions, resulting in altered interactions with downstream signaling pathways[2]. Specific small-molecule inhibitors that covalently target the mutant serine have been developed in early studies, and allele-selective genome-editing approaches have demonstrated experimental efficacy in selectively inhibiting tumor cell growth by disrupting the mutant allele[1][4]. The presence of the KRAS G12S mutation serves as both a therapeutic target and a biomarker for patient stratification. However, therapeutic challenges include achieving sufficient selectivity for the mutant protein over the wild-type and managing potential resistance mechanisms and on-target toxicity[1][4].

Other names

KRAS G12S mutantKRAS p.G12SK-Ras G12SKRAS glycine 12 serine mutant

Covalent inhibition of KRAS G12S mutant by small molecules that acylate the mutant serine. Allele-specific genome editing to disrupt mutant allele and suppress tumor cell growth.