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

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.

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Publication Details

Journal
Cancer Discovery
Published
2026-09-29
DOI
https://doi.org/10.1158/2159-8290.cd-25-1596
Primary Topic
Melanoma and MAPK Pathways
Type
article
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article

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

Beau Baars, Christos Adamopoulos, Nayeli Gutiérrez, Ziyue Kou et al.
Cancer Discovery
Melanoma and MAPK Pathways
article

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

Beau Baars, Christos Adamopoulos, Nayeli Gutiérrez, Ziyue Kou, Kevin Mohammed, Tiphaine C. Martin, Evripidis Gavathiotis, Jian Jun Jin, Evangelia Matenoglou, Stuart A. Aaronson, Ana Orive-Ramos, Sílvia Coma, Ernesto Guccione, Jonathan A. Pachter, Bijaya Gaire, Poulikos I. Poulikakos, Mathieu Desaunay
article en

Abstract

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.

Cancer Discovery
Albert Einstein College of Medicine (US), National and Kapodistrian University of Athens (GR), Verastem (United States) (US), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 20%
Melanoma and MAPK Pathways
DOISourceOpenAlex
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