Rat sarcoma virus GTPase (RAS) (RAS)

Rat sarcoma virus (RAS) proteins are a family of small GTPases that serve as critical molecular switches in cellular signal transduction. They cycle between an inactive GDP-bound state and an active GTP-bound state to relay signals from cell surface receptors to downstream pathways, primarily the MAPK/ERK and PI3K/AKT cascades, which regulate cell growth, survival, and differentiation. In approximately 30% of human cancers, missense mutations—most frequently at codons 12, 13, and 61—render the RAS protein constitutively active by impairing its ability to hydrolyze GTP. This persistent activation drives uncontrolled cellular proliferation and tumorigenesis, particularly in high-mortality cancers such as pancreatic, colorectal, and non-small cell lung cancer. Although RAS was long considered an 'undruggable' target due to its smooth surface and picomolar affinity for GTP, the recent development of covalent inhibitors specifically targeting the KRAS G12C mutant has proven the feasibility of direct RAS inhibition. Ongoing therapeutic efforts now focus on expanding these successes to other common mutants like G12D and G12V and developing pan-RAS inhibitors to address the broad landscape of RAS-driven malignancies.

Other names

p21 proteinKirsten rat sarcoma viral oncogene homolog (KRAS)Harvey rat sarcoma viral oncogene homolog (HRAS)Neuroblastoma rat sarcoma viral oncogene homolog (NRAS)Small GTP-binding protein

Drugs targeting RAS mutants typically act by covalently binding to specific mutant residues (e.g., Cys12 in G12C) to lock the protein in its inactive GDP-bound state, inhibiting the exchange of GDP for GTP, or disrupting interactions between RAS and its downstream effectors like RAF and PI3K. Other strategies include inhibiting farnesyltransferase to prevent the necessary post-translational membrane localization of RAS proteins.