Drugging the undruggable RAS: Mission Possible?

Attempts to target RAS pharmaceutically have not yet yielded small molecules with sufficient potency and drug-like characteristics to be useful, but additional approaches are underway.Inhibitors of RAS membrane interaction and subcellular localization remain attractive targets for therapeutic intervention. In this regard, recent discoveries of functionally relevant post-translational modifications of RAS, such as phosphorylation and ubiquitylation, suggest new opportunities to block RAS function.Inhibitors of RAS effector signalling are currently centred on the RAF–MEK–ERK and PI3K–AKT–TOR pathways, with many inhibitors of components of these two pathways under clinical evaluation. The less well-studied effector pathways that lead to activation of RAL and RAC small GTPases are also promising targets.Despite some setbacks owing to issues of reproducibility, functional screens for synthetic lethal interactors with oncogenic RAS remain an attractive approach to identify novel drug targets for RAS-driven cancers.RAS-driven cancers become efficient scavengers of nutrients and may rely on pathways such as autophagy and macropinocytosis. Furthermore, oncogenic KRAS has a crucial role in altering tumour metabolism, including rewiring of both glucose- and glutamine-dependent metabolic pathways. These alterations could provide the opportunity for novel therapeutic interventions.Inhibitors of RAS membrane interaction and subcellular localization remain attractive targets for therapeutic intervention. In this regard, recent discoveries of functionally relevant post-translational modifications of RAS, such as phosphorylation and ubiquitylation, suggest new opportunities to block RAS function.RAS-driven cancers become efficient scavengers of nutrients and may rely on pathways such as autophagy and macropinocytosis. Furthermore, oncogenic KRAS has a crucial role in altering tumour metabolism, including rewiring of both glucose- and glutamine-dependent metabolic pathways. These alterations could provide the opportunity for novel therapeutic interventions.