G13D

G13D refers to a specific missense mutation in the KRAS gene, in which glycine at codon 13 is replaced by aspartic acid (G13D). It is an activating mutation that occurs in exon 2 of KRAS and contributes to constitutive signaling through the RAS-RAF-MAPK and PI3K-AKT pathways, promoting cell growth and survival.

Occurrence and context: KRAS mutations are common in several cancers, most notably colorectal, pancreatic, and lung cancers. In colorectal cancer, KRAS mutations occur in about 40% of cases, with G13D being one of several substitutions at codon 13. It is less frequent than some G12 substitutions but is among the well-described exon 2 alterations.

Clinical significance: In metastatic colorectal cancer, activating KRAS mutations generally predict lack of response to anti-EGFR therapies such as cetuximab and panitumumab. Early studies suggested that the G13D mutation might respond differently to anti-EGFR therapy compared with other KRAS mutations, but larger and more recent analyses have not consistently confirmed a unique benefit. Consequently, most guidelines categorize all activating KRAS exon 2 mutations (codons 12 and 13) as predictive of nonresponse to anti-EGFR therapy, though research continues. Prognostic implications of G13D are also variable across studies, with some reporting outcomes closer to wild-type and others showing no clear advantage.

Therapeutic landscape: Direct inhibitors targeting KRAS G13D are not established in routine practice. In contrast to emerging G12C-targeted therapies, there are no approved G13D-specific agents, and treatment decisions rely on broad KRAS/NRAS testing and standard treatment frameworks. Ongoing research includes exploring combination strategies and alternative targets within downstream pathways.

See also: KRAS mutations, codon 12, codon 13, anti-EGFR therapy, metastatic colorectal cancer.