Ras small GTPase family (RAS) (RAS)

The Ras small GTPase family consists of a group of related proteins that function as binary molecular switches in cellular signal transduction [1.1.2, 1.2.4]. These proteins cycle between an active, GTP-bound state and an inactive, GDP-bound state, a process regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) [1.1.5, 1.3.1]. When active, Ras proteins recruit and activate downstream effectors such as RAF kinases and PI3K, which drive essential processes including cell proliferation, survival, and differentiation [1.1.3, 1.3.3]. Mutations that lock Ras in a constitutively active state are found in approximately 30% of all human cancers, with KRAS, NRAS, and HRAS being the most frequently implicated isoforms [1.2.4, 1.3.5]. These mutations are particularly prevalent in pancreatic, colorectal, and lung cancers, making Ras a high-priority therapeutic target [1.2.2, 1.3.5]. Although long considered "undruggable," recent pharmacological advances have produced covalent inhibitors that specifically target the KRAS G12C mutation by trapping the protein in its inactive state [1.3.3, 1.4.2]. Additionally, germline mutations in Ras family members or their regulators lead to a spectrum of developmental disorders collectively termed RASopathies [1.1.2, 1.4.1]. Therapeutic strategies also include targeting upstream regulators like SOS1 or downstream effectors to overcome resistance and feedback loops [1.3.1, 1.3.4].

Other names

HRASKRASNRASRalRapRhebRadRitRat sarcoma virus oncogene familyp21 Ras

Covalent inhibition of the inactive GDP-bound state (e.g., KRAS G12C inhibitors), inhibition of farnesyltransferase to prevent membrane localization, inhibition of SOS1 to block nucleotide exchange, and allosteric modulation of effector binding.