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
Ana Orive-Ramos, Bijaya Gaire, Christos Adamopoulos, Beau Baars, Mathieu Desaunay, Ziyue Kou, Evangelia Matenoglou, Silvia Coma, Nayeli Gutiérrez Trejo, Kevin Mohammed, Stuart A. Aaronson, Jian Jin, Tiphaine C. Martin, Ernesto Guccione, Evripidis Gavathiotis, Jonathan A. Pachter, Poulikos I. PoulikakosAbstract
Effective MAPK-targeted therapies require greater pathway inhibition in tumors than in normal tissues. Although pan-RAF inhibitors have demonstrated activity in RAS-mutant cancers, combinations with MEK inhibitors require dose reductions because of toxicity, limiting clinical benefit. Here, we show that this toxicity results from MEK inhibitor-mediated feedback relief, which promotes RAF activation and enhances pan-RAF inhibitor binding in normal cells. We identify a distinct mechanism of RAF inhibition by RAF/MEK glues: by stabilizing RAF-MEK complexes, these compounds trap RAF in the cytosol, preventing membrane recruitment required for RAF activation. This spatial modulation mechanism preserves tumor-selective MAPK inhibition and enables full-dose combination therapy with pan-RAF inhibitors. This therapeutic strategy produced robust tumor regressions in multiple RAS-mutant tumor models, including models refractory to current RAS/MAPK-targeting therapies. Our findings underscore drug-induced proximity as a strategy to achieve tumor selectivity and support the clinical development of RAF/MEK glue plus pan-RAF inhibitor combinations for RAS-mutant tumors.