KRAS

KRAS is a gene encoding a small GTPase of the Ras superfamily. The encoded KRAS protein acts as a molecular switch in intracellular signaling, cycling between an active GTP-bound form and an inactive GDP-bound form. Activation is promoted by guanine nucleotide exchange factors (GEFs) such as SOS1, while GTP hydrolysis is accelerated by GTPase-activating proteins (GAPs) including NF1. In its active state, KRAS relays signals to multiple downstream pathways, notably the MAPK/ERK, PI3K-AKT/mTOR, and RalGEF pathways, influencing cell proliferation, differentiation, and survival.

There are two major KRAS splice variants, KRAS4A and KRAS4B, which produce slightly different C-terminal tails and membrane-targeting properties. The C-terminus contains a CAAX motif; post-translational modifications such as farnesylation and, for some variants, palmitoylation, facilitate membrane association essential for signaling.

KRAS is frequently mutated in human cancers. Oncogenic mutations often occur at codons 12, 13, or 61, with substitutions such as G12D, G12V, and G13D common. These mutations reduce GTPase activity or impede GTP hydrolysis, locking KRAS in a constitutively active state and driving uncontrolled signaling. Histologically, KRAS mutations are especially prevalent in pancreatic, colorectal, and lung cancers. For decades, direct targeting of mutant KRAS was challenging, but recently covalent inhibitors targeting KRAS G12C (for example, sotorasib and adagrasib) have been approved for certain KRAS G12C-mutant cancers, with ongoing trials addressing resistance and combination strategies.

KRAS remains a focus of cancer biology and targeted therapy research. Beyond oncogenesis, KRAS participates in normal development and tissue homeostasis, and its signaling integrates with receptor tyrosine kinases and other small GTPases.