Kirsten rat sarcoma virus oncogene homolog (KRAS) mutants (KRAS)

Kirsten rat sarcoma virus oncogene homolog (KRAS) is a small GTPase that functions as a critical molecular switch in the RAS/MAPK and PI3K/AKT signaling pathways, regulating cell growth, differentiation, and survival (UniProt P01116; NIH NCI). Mutations at codon 12, such as G12C, G12D, and G12V, impair the intrinsic GTPase activity and prevent GTPase-activating proteins (GAPs) from promoting GTP hydrolysis, thereby locking KRAS in a constitutively active, GTP-bound state (PubMed PMID: 33479115). These mutations are prevalent in several lethal malignancies, including pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer (PubMed PMID: 34545132). While KRAS was long considered "undruggable" due to its high affinity for GTP and lack of deep binding pockets, the discovery of a cryptic pocket (the Switch II pocket) enabled the development of allele-specific covalent inhibitors for G12C (Nature Reviews Drug Discovery). Current therapeutic strategies have expanded to include non-covalent inhibitors for G12D and G12V, as well as "multi-RAS" inhibitors that target the active (ON) state of multiple KRAS mutants (PubMed PMID: 37072481). These advancements represent a significant shift in precision oncology, offering targeted options for patients who previously relied on broad-spectrum chemotherapy.

Other names

KRAS proto-oncogene, GTPasep21 RasK-Ras 2Kirsten rat sarcoma viral oncogene homolog

Allele-specific covalent inhibition of the Switch II pocket (G12C), non-covalent inhibition of the GDP-bound (OFF) or GTP-bound (ON) states, and disruption of effector protein interactions (Nature Reviews Drug Discovery; PubMed PMID: 33479115).