GTPase KRas G12D mutant (KRAS G12D) (KRAS G12D)

KRAS G12D is a specific oncogenic mutant of the KRAS protein, a member of the small GTPase family that acts as a molecular switch in cell signaling. The G12D mutation involves a substitution of glycine with aspartic acid at codon 12, which impairs the protein's intrinsic GTPase activity and renders it insensitive to GTPase-activating proteins (GAPs). This results in the protein being constitutively locked in an active, GTP-bound state, driving persistent signaling through the MAPK/ERK and PI3K/AKT pathways to promote uncontrolled cell growth, survival, and metastasis. KRAS G12D is the most prevalent KRAS mutation in human cancers, particularly dominant in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). Historically considered undruggable due to its high affinity for GTP and lack of traditional small-molecule binding pockets, recent therapeutic breakthroughs have introduced several novel strategies. These include non-covalent small-molecule inhibitors that form salt bridges with the mutant aspartic acid residue, targeted protein degraders (PROTACs) that recruit E3 ligases to destroy the mutant protein, and peptide-based vaccines or adoptive cell therapies that target the mutant peptide sequence as a neoantigen. These treatments aim to either directly inhibit the mutant protein's signaling or leverage the immune system to recognize and eliminate cells harboring the G12D mutation.

Other names

Kirsten rat sarcoma virus oncogene homolog G12DKRAS proto-oncogene, GTPase G12Dp21 protein G12DK-Ras 2 G12DKRAS G12D mutant neoantigen

Inhibition of GTPase activity through non-covalent binding (e.g., salt-bridge formation with Asp12), targeted protein degradation via PROTACs, gene silencing via siRNA, or induction of a neoantigen-specific immune response through vaccines or TCR-T cell therapies [1.1.2, 1.3.1, 1.3.3, 1.3.4].