Rat sarcoma virus family small GTPase (RAS)

The RAS family GTPases, primarily comprising KRAS, HRAS, and NRAS, are small membrane-associated proteins that function as molecular switches in signal transduction pathways. They cycle between an active GTP-bound state and an inactive GDP-bound state to regulate fundamental cellular processes such as growth, division, and survival through the MAPK and PI3K pathways (UniProt, 2024; NIH, 2023). Mutations in RAS genes are among the most common drivers in human cancers, particularly in pancreatic, colorectal, and lung carcinomas, where they lead to constitutive signaling and uncontrolled cell proliferation (PubMed, 2022). Historically considered undruggable due to their high affinity for GTP and lack of deep binding pockets, recent therapeutic breakthroughs have led to the development of allele-specific covalent inhibitors, such as those targeting the KRAS G12C mutation, which have successfully entered clinical practice (Nature, 2021).

Other names

RAS GTPasep21rasRAS superfamilyTransforming protein p21GTP-binding protein RAS

Drugs targeting RAS family GTPases typically act as covalent inhibitors that lock the protein in its inactive GDP-bound state (e.g., KRAS G12C inhibitors), or as farnesyltransferase inhibitors that prevent the post-translational modification required for membrane localization and activation (National Cancer Institute, 2023; Nature Reviews Drug Discovery, 2022).