Kirsten rat sarcoma virus proto-oncogene (KRAS) G12 mutants (KRAS G12X)

Kirsten rat sarcoma virus proto-oncogene (KRAS) is a small GTPase that functions as a critical molecular switch in cell signaling, cycling between an inactive GDP-bound state and an active GTP-bound state to regulate pathways such as MAPK/ERK and PI3K/AKT [1]. Mutations at the glycine 12 position (G12X), including G12C, G12D, and G12V, are the most common oncogenic drivers in human cancers, particularly in pancreatic, lung, and colorectal adenocarcinomas [2]. These mutations impair the protein's intrinsic GTPase activity and render it insensitive to GTPase-activating proteins (GAPs), locking it in a constitutively active state that drives uncontrolled cell proliferation and survival [3]. While KRAS was long considered undruggable, the discovery of a targetable switch-II pocket led to the development of allele-specific covalent inhibitors like sotorasib and adagrasib for the G12C variant [4]. Current therapeutic strategies are expanding to include non-covalent inhibitors for G12D, pan-RAS inhibitors that target the active 'on' state, and PROTAC-mediated degradation [2, 5]. Despite these advances, clinical efficacy is often limited by the rapid emergence of acquired resistance through secondary mutations or bypass signaling activation [4]. Patient selection for these therapies relies on molecular profiling to identify specific G12 variants, as many inhibitors are allele-specific [3]. Safety profiles for current inhibitors frequently include gastrointestinal toxicities and hepatotoxicity, necessitating careful clinical monitoring [4].

Other names

KRAS G12CKRAS G12DKRAS G12VKRAS G12RKRAS G12SKRAS G12Ap.G12XKRAS codon 12 mutants

Covalent and non-covalent inhibition of the switch-II pocket, trapping the protein in an inactive GDP-bound state or inhibiting the active GTP-bound state, as well as targeted protein degradation (PROTAC) and mutant-specific immunotherapy.