Ras proto-oncogene GTPase (RAS) (RAS)

RAS proteins (KRAS, NRAS, and HRAS) are small GTPases that function as binary molecular switches in signal transduction pathways controlling cell growth, differentiation, and survival (PubMed: 25772324). They cycle between an active GTP-bound state and an inactive GDP-bound state; however, oncogenic mutations lock these proteins in the active state, driving uncontrolled proliferation (NIH: National Cancer Institute). The term "RAS-addicted tumor cells" refers to a phenotype where cancer cells become physiologically dependent on this constitutive signaling for their continued viability, a concept known as oncogene addiction (PubMed: 21566165). While RAS was long considered "undruggable" due to its high affinity for GTP and lack of traditional binding pockets, recent breakthroughs led to the development of covalent inhibitors targeting specific mutations like KRAS G12C (Nature: 503, 548–551). These therapeutic agents, such as sotorasib and adagrasib, lock the protein in its inactive GDP-bound conformation, effectively inducing apoptosis in addicted cells by disrupting the MAPK/ERK and PI3K/AKT signaling cascades (PubChem: Sotorasib). Resistance remains a significant challenge, often occurring through the upregulation of bypass signaling pathways or secondary mutations in the RAS protein itself (PubMed: 34161861). Consequently, current research focuses on combination therapies and the development of "pan-RAS" inhibitors to address a broader range of mutations (PubMed: 35914461).

Other names

RAS-addicted tumor cellsKRASNRASHRASp21 RasRas oncogene familyRat sarcoma virus oncogene

Direct covalent inhibition of the inactive GDP-bound state of specific mutant forms (e.g., KRAS G12C) or inhibition of downstream effector pathways such as MAPK/ERK and PI3K/AKT to disrupt oncogenic signaling.