Rat sarcoma virus oncogene mutant proteins (RAS) (RAS)

Oncogenic Ras mutant proteins are a family of membrane-associated small GTPases, including KRAS, HRAS, and NRAS, that act as pivotal molecular switches in intracellular signaling pathways such as MAPK/ERK and PI3K/AKT (Simanshu et al., 2017, Cell). Under physiological conditions, these proteins cycle between an active GTP-bound state and an inactive GDP-bound state to regulate cell growth and differentiation. Point mutations, most commonly occurring at codons 12, 13, or 61, lock the protein in a constitutively active GTP-bound conformation, driving the uncontrolled proliferation and survival characteristic of many human cancers (Prior et al., 2020, Cancer Cell). These mutations are particularly prevalent in pancreatic, colorectal, and lung adenocarcinomas. In the context of immunotherapy, these mutant proteins serve as neoantigens because they are processed into peptides and presented on the cell surface by Major Histocompatibility Complex (MHC) molecules, allowing for targeted recognition by the immune system (Wang et al., 2021, Journal of Hematology & Oncology). Recent therapeutic advances include the development of allele-specific covalent inhibitors, such as those targeting KRAS G12C, as well as neoantigen-directed vaccines and TCR-engineered T-cell therapies (Canon et al., 2019, Nature).

Other names

Oncogenic Ras mutant antigensMutant RASRAS neoantigensKRAS/NRAS/HRAS mutantsOncogenic RAS

Covalent inhibition of the switch II pocket in the GDP-bound state of mutant RAS proteins or T-cell mediated recognition of mutant RAS peptides presented on MHC molecules.