Kirsten rat sarcoma viral proto-oncogene protein (KRAS)

Kirsten rat sarcoma viral proto-oncogene protein (KRAS) is a small GTPase enzyme belonging to the Ras family, acting as a molecular switch in cellular signal transduction[1][3][5][6]. The KRAS protein cycles between active (GTP-bound) and inactive (GDP-bound) states, relaying extracellular signals (from growth factors, cytokines, or receptor tyrosine kinases) for cell growth, proliferation, differentiation, and apoptosis[1][2][3]. Oncogenic mutations in KRAS (especially at codons 12, 13, and 61) disrupt normal GTPase activity, resulting in constitutive activation, sustained proliferative signaling, immune evasion, and tumorigenesis—most notably in lung, pancreatic, and colorectal cancers[1][4][6]. The protein is typically membrane-bound due to post-translational modifications and interacts with effectors such as RAF, PI3K, and RalGEF to activate the downstream MAPK/ERK and PI3K/AKT/mTOR pathways, among others[3][4]. Drugs targeting mutant KRAS, such as sotorasib and adagrasib, have recently become available and act through covalent inhibition of specific KRAS mutations[3]. Safety and efficacy challenges include emergence of drug resistance mechanisms, toxicity due to effects on healthy cell growth, and variable response based on tumor mutation status[4][6]. KRAS mutations are routinely tested as biomarkers in oncology for therapeutic decision-making and prognostic assessment[5].

Other names

K-RasKRASc-K-rasRasKRAS4AKRAS4Bp21RAS

Covalent inhibition of mutant KRAS (G12C) by occupying the switch II pocket and locking KRAS in its inactive GDP-bound state Downstream pathway inhibition (e.g., MEK or PI3K inhibitors), often indirect