Spatial modulation of RAF by RAF/MEK glue enables full-dose combination with pan-RAF inhibitor and potent RAS-mutant tumor-selective MAPK and growth inhibition

The clinical benefit of MAPK-targeted therapies depends on greater pathway inhibition in tumors than normal tissues. Although pan-RAF inhibitors are active in RAS-mutant cancers, combining them with MEK inhibitors requires dose reductions due to toxicity, limiting efficacy. We show the toxicity results from MEK inhibitor–mediated feedback relief, which promotes RAF activation and pan-RAF inhibitor engagement in normal cells, narrowing the therapeutic index. We further demonstrate that MEK is exclusively cytosolic, and RAF/MEK glues overcome this limitation through spatial trapping. By stabilizing cytosolic RAF–MEK complexes, RAF/MEK glues prevent feedback-driven RAF activation in normal cells while maintaining inhibition of oncogenic RAF signaling in RAS-mutant tumors, where RAF is constitutively activated at the plasma membrane. Consequently, this enables full-dose combination with pan-RAF inhibitors, resulting in deeper MAPK suppression and robust tumor regressions in RAS-mutant models. Thus, by spatially controlling wild-type effectors, drug-induced proximity can be harnessed to increase tumor selectivity of pathway-targeted therapies.