Authors
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 Poulikakos
Published in
Cancer discovery. Sep 29, 2026. Epub Sep 29, 2026.
Abstract
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.
PMID:
42810411
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.
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