RAS proto-oncogene protein (RAS)

RAS proto-oncogene proteins (KRAS, HRAS, and NRAS) are small GTPases that function as essential molecular switches in cellular signal transduction [1.3.1, 1.3.3]. They cycle between an active GTP-bound state and an inactive GDP-bound state to regulate critical pathways such as MAPK/ERK and PI3K/AKT, which govern cell growth, differentiation, and survival [1.3.1, 1.4.2]. Mutations in RAS genes, particularly at codons 12, 13, and 61, are found in approximately 30% of all human cancers, including over 90% of pancreatic ductal adenocarcinomas and 40% of colorectal cancers [1.3.2, 1.4.1]. These mutations typically impair the protein's intrinsic GTPase activity, leading to constitutive activation and uncontrolled oncogenic signaling [1.1.1, 1.3.2]. While historically considered "undruggable," the development of covalent inhibitors like sotorasib and adagorasib has successfully targeted the KRAS G12C mutation by locking the protein in its inactive state [1.1.5, 1.2.3]. More recently, "RAS(ON)" inhibitors such as daraxonrasib have emerged to target the active state of multiple RAS variants, offering a broader therapeutic approach for RAS-driven malignancies [1.1.4].

Other names

p21c-rasKRASHRASNRASRat sarcoma proteinGTPase KRasGTPase HRasGTPase NRas

Inhibition of RAS signaling by either covalently binding to the inactive GDP-bound state (specifically for KRAS G12C) or non-covalently binding to the active GTP-bound state (RAS-multi inhibitors), which prevents interaction with downstream effectors such as RAF, PI3K, and RalGDS.