G12D

G12D is a specific missense mutation in the KRAS gene in which glycine (G) at codon 12 is replaced by aspartic acid (D). This substitution alters the KRAS protein, a small GTPase that transduces signals from cell-surface receptors to downstream pathways. G12D variants typically reduce intrinsic GTPase activity and promote constitutive activation of KRAS, keeping it in a GTP-bound state. As a result, cells experience ongoing signaling through pathways such as MAPK/ERK and PI3K/AKT, which can drive proliferation, survival, and tumorigenesis.

G12D is among the more frequent KRAS codon 12 substitutions seen across several cancers, with notable prevalence in pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma. The presence of KRAS mutations, including G12D, is often associated with poorer prognosis in some cancer types and, in colorectal cancer, predicts a lack of response to anti-EGFR therapies, influencing treatment decisions.

Therapeutic development for G12D has focused on direct targeting and on combination strategies. Historically challenging to target KRAS directly, the landscape as of the mid-2020s includes ongoing research into G12D-selective inhibitors (such as MRTX1133 in preclinical and early clinical evaluation) as well as approaches that inhibit parallel or downstream signaling, including SHP2 and MEK inhibitors. No universally approved G12D-specific therapy existed yet, and management typically adheres to established guidelines for KRAS-mutant cancers, with consideration of mutation status in treatment planning.