Kirsten rat sarcoma virus proto-oncogene (KRAS)

The Kirsten rat sarcoma virus proto-oncogene (KRAS) encodes a small GTPase that functions as a molecular switch, cycling between active GTP-bound and inactive GDP-bound states to regulate intracellular signaling [1]. It is a central component of the MAPK/ERK and PI3K/AKT pathways, which govern essential cellular processes including proliferation, differentiation, and survival [2]. Mutations in KRAS, most frequently occurring at codon 12, result in impaired GTP hydrolysis, locking the protein in a constitutively active state that drives oncogenic transformation [3]. These mutations are prevalent in some of the most lethal human malignancies, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer [4]. For decades, KRAS was deemed "undruggable" due to its smooth surface and picomolar affinity for GTP, which hindered the development of traditional small-molecule inhibitors [5]. However, the discovery of a cryptic pocket in the KRAS G12C mutant allowed for the development of covalent inhibitors that trap the protein in its inactive conformation [6]. Current therapeutic strategies focus on these allele-specific inhibitors, though challenges such as primary and acquired resistance remain significant hurdles in clinical management [7].

Other names

KRAS2RASK2KI-RASc-K-rasK-Ras 2Kirsten rat sarcoma 2 viral oncogene homologGTPase KRas

Covalent inhibition of the KRAS G12C mutant protein, locking it in the inactive GDP-bound conformation and preventing downstream signaling through the MAPK and PI3K pathways.