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

The KRAS G12S mutant is a specific oncogenic variant of the Kirsten rat sarcoma viral oncogene homolog (KRAS), a small GTPase that functions as a molecular switch in cell signaling [1.4.2, 1.5.5]. In this mutant, a glycine residue at position 12 is substituted with serine, which impairs the protein's ability to hydrolyze GTP and renders it insensitive to GTPase-activating proteins (GAPs) [1.4.2, 1.5.1]. Consequently, the KRAS G12S protein remains constitutively in its active, GTP-bound state, leading to the persistent activation of downstream pathways such as MAPK/ERK and PI3K/AKT/mTOR [1.4.2, 1.5.2]. This chronic signaling drives the hallmarks of cancer, including uncontrolled cell proliferation, survival, and metabolic reprogramming [1.5.4, 1.5.5]. While less prevalent than the G12C or G12D mutations, KRAS G12S is a significant driver in colorectal, lung, and pancreatic cancers [1.5.1, 1.5.4]. Historically considered undruggable, this mutant is now being targeted by next-generation multi-selective RAS inhibitors, such as RMC-6236 (daraxonrasib), which utilize a tri-complex mechanism to inhibit the active state of the protein [1.1.2, 1.2.5]. Additionally, experimental approaches involving CRISPR/Cas9 gene editing and siRNA-mediated knockdown are being explored to specifically deplete the mutant allele [1.5.1, 1.5.4].

Other names

KRAS G12Sp.G12Sc.34G>AKirsten rat sarcoma virus oncogene homologKRAS proto-oncogene, GTPasep21 proteinKRAS2RASK2

RMC-6236 (daraxonrasib) is a RAS(ON) multi-selective inhibitor that binds to the active, GTP-bound state of various KRAS mutants, including G12S, by forming a tri-complex with cyclophilin A, thereby sterically hindering the interaction between KRAS and its downstream effectors [1.2.5, 1.4.5].