{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:02:13Z","timestamp":1790726533821,"version":"4.1.0"},"reference-count":0,"publisher":"American Association for Cancer Research (AACR)","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1158\/2159-8290.cd-25-1596","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:17:42Z","timestamp":1790723862000},"update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["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"],"prefix":"10.1158","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6321-3422","authenticated-orcid":false,"given":"Ana","family":"Orive-Ramos","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a9tmd77","id-type":"ROR","asserted-by":"publisher"}],"name":"Icahn School of Medicine at Mount Sinai 1 New York, 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