{
  "abstract": "Therapeutic inhibition of the RAS/MAPK cascade, an oncogenic driver in over one-third of human cancers, has been limited by a core trade-off: effective pathway blockade in tumors versus dose-limiting toxicity in normal tissues. Although Type 1.5 RAF inhibitors successfully mitigated this trade-off in BRAF-monomer-driven tumors, an equivalent strategy has been lacking for RAF-dimer-driven cancers, including those with RAS mutations. Here, we characterize ELV-3111, a next-generation, potent, and selective Type 1 RAF inhibitor that overcomes this limitation via a distinct mechanism of action. ELV-3111 induces paradoxical MAPK hyperactivation in normal tissues by binding RAF and promoting the active conformation (priming) followed by rapid dissociation (fast off-rate), a biochemical feature that spares RAS-mutant tumors, where RAF is already primed. In these and other RAF dimer-driven tumor models, ELV-3111 achieves potent and selective MAPK and growth suppression. When combined with a MEK inhibitor, ELV-3111 enables complementary pharmacology: additive inhibition in tumors and compensatory effects in normal tissues. The combination produced durable regressions across RAS-mutant and BRAF-mutant models, including a RAS-mutant model refractory to current therapies, while maintaining favorable tolerability. Thus, we uncover a generalizable mechanism that enables Type 1 RAF inhibitor plus MEK inhibitor combinations to achieve tumor-selective MAPK suppression, with the potential to inform targeted therapy design.",
  "abstract_shown": true,
  "affiliations": [
    "Icahn School of Medicine at Mount Sinai, NY, USA"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "M. Desaunay"
    },
    {
      "name": "T. Peters"
    },
    {
      "name": "E. Matenoglou"
    },
    {
      "name": "B. Baars"
    },
    {
      "name": "B. Gaire"
    },
    {
      "name": "A. Orive-Ramos"
    },
    {
      "name": "L. ren"
    },
    {
      "name": "J. P. Lyssikatos"
    },
    {
      "name": "M. R. Burkard"
    },
    {
      "name": "D. Dacus"
    },
    {
      "name": "M. J. Sale"
    },
    {
      "name": "S. A. Aaronson"
    },
    {
      "name": "F. McCormick"
    },
    {
      "name": "E. Gavathiotis"
    },
    {
      "name": "S. Gross"
    },
    {
      "affs": [
        0
      ],
      "name": "P. I. Poulikakos"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d2fpmq804fjpf.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.05.756774",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.05.756774v1.full",
  "id": "d2fpmq804fjpf",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.05.756774v1",
  "language": null,
  "licence": "CC-BY-ND",
  "licence_label": "CC BY-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "1312|Melanoma and MAPK Pathways"
    ]
  ],
  "openalex": "W7220675282",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.05.756774v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/d2fpmq804fjpf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:14Z",
      "native_id": "10.64898/2026.10.05.756774",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.05.756774v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Binding kinetics enable tumor-selective MAPK and growth suppression by a Type 1 RAF Inhibitor",
  "title_text": "Binding kinetics enable tumor-selective MAPK and growth suppression by a Type 1 RAF Inhibitor",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:14Z",
  "url": "https://research.draconitic.com/paper/d2fpmq804fjpf",
  "venue": "bioRxiv",
  "versions": []
}