Kirsten rat sarcoma virus oncogene homolog G12X mutant (KRAS G12X)

KRAS (Kirsten rat sarcoma virus oncogene homolog) is a small GTPase that functions as a molecular on/off switch, regulating critical cellular signaling pathways such as MAPK/ERK and PI3K/AKT. Mutations at codon 12 (G12X, where X represents various amino acids like C, D, V, R, A, or S) are the most frequent oncogenic drivers in human cancers, particularly in pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. These mutations impair the protein's intrinsic GTPase activity and its response to GTPase-activating proteins (GAPs), locking KRAS in a constitutively active, GTP-bound state that promotes uncontrolled cell growth and survival. While allele-specific inhibitors like sotorasib and adagrasib target the G12C mutation specifically, newer therapeutic strategies involve 'multi-RAS' or 'RAS-ON' inhibitors like RMC-6236, which are designed to target the broader class of G12X mutants. These advancements aim to provide treatment options for patients with G12D, G12V, and other non-G12C mutations that were previously considered undruggable.

Other names

KRAS codon 12 mutantKRAS G12 mutantKRAS G12XKRAS G12C/D/V/R/A/S

Non-covalent RAS-ON inhibition (for G12X), Covalent inhibition (for G12C), Allosteric inhibition