Kirsten rat sarcoma viral oncogene homolog G12V mutant protein (KRAS G12V)

The **Kirsten rat sarcoma viral oncogene homolog G12V mutant protein** (KRAS G12V) is an oncogenic variant of the small **GTPase enzyme** encoded by the *KRAS* gene. The substitution at codon 12 from glycine to valine results in constitutive activation by impairing intrinsic **GTPase activity**, locking it predominantly in its active, **GTP-bound state**. This leads to persistent stimulation of multiple downstream pathways—most notably RAF-MEK‑ERK and PI3K-Akt—that drive uncontrolled cell proliferation, survival, motility, and tumorigenesis. The *KRAS* gene is among the most frequently mutated proto-oncogenes across human cancers; mutations at codon 12 account for over three-fourths of all *KRAS* mutations seen clinically. The **G12V mutation** is especially prevalent in pancreatic (~88%), colorectal (~50%), and lung (~32%) cancers. Direct pharmacological targeting has been historically challenging due to a lack of suitable binding pockets on its surface; however, recent advances include engineered peptides/proteins that induce misfolding/aggregation or block critical interactions with effectors. These approaches have shown preclinical efficacy but face hurdles related to specificity and delivery.[1][2][3][4]

Other names

KRAS G12VKRasG12VOncogenic KRAS mutant (G12V)Kirsten-Ras oncogene homolog, G12V mutation

Inhibition of downstream signaling by blocking effector binding or inducing misfolding/aggregation to inactivate the protein[1][3]. Peptides/miniproteins can bind to the GDP-bound inactive state or remodel the effector domain to prevent activation and signaling[3][6].