{
  "abstract": "Acquired resistance to mitogen-activated protein kinase (MAPK) pathway inhibitors remains a major barrier to durable control of BRAF-mutant melanoma. Although resistance mechanisms are heterogeneous, they converge on adaptive programs that support survival, phenotypic plasticity, and metabolic fitness. We asked whether eukaryotic translation initiation factor 4A (eIF4A)-dependent mRNA translation represents a shared vulnerability of kinase inhibitor-resistant melanoma. Using matched BRAFV600E A375 and BRAF inhibitor-resistant A375R cells together with additional melanoma models, we integrated pharmacological and functional assays with polysome-associated RNA sequencing, quantitative proteomics, bioenergetic profiling, metabolomics, [U-13C5]glutamine tracing, and xenograft studies. Melanoma cells remained sensitive to multiple eIF4A inhibitors regardless of their responsiveness to BRAF inhibition. The eIF4A inhibitor CR-1-31-B rapidly reduced nascent protein synthesis when used alone in A375 cells and when added to the BRAF inhibitor PLX4032 in A375R cells; it also reduced BCL-2, CDK4, and cyclin D3 abundance, suppressed clonogenic growth, and induced apoptosis. Integrated analysis showed that acquired resistance involved broad RNA-abundance remodeling with superimposed changes in translational efficiency and buffering, affecting survival, extracellular-matrix and plasticity programs, and mitochondrial and metabolic functions. In resistant cells, CR-1-31-B induced early transcript-selective translational changes, accompanied at later time points by RNA-abundance and proteome remodeling. Publicly annotated 5' untranslated regions (5'UTRs) of CR-1-31-B-sensitive transcripts were enriched for purine-rich sequence architecture and local structural complexity. eIF4A inhibition preferentially attenuated the expression of proteins acquired during resistance and imposed a lower-output metabolic state in sensitive and resistant cells, reducing tricarboxylic-acid-cycle and pentose-phosphate-pathway metabolite pools and restricting intracellular glutamine-carbon transfer downstream of uptake. In A375 xenografts, CR-1-31-B delayed tumor growth, while its combination with PLX4720 produced deeper and more sustained tumor control and prolonged tumor endpoint-free survival compared with PLX4720 alone. These findings show that multiple resistance-associated programs spanning signaling, cell survival, and metabolism share a dependency on eIF4A-dependent translation and provide a preclinical rationale to test whether adding eIF4A inhibition can prolong responses to MAPK-targeted therapy in melanoma.",
  "abstract_shown": true,
  "affiliations": [
    "University of Montreal"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "name": "A. Schcolnik-Cabrera"
    },
    {
      "name": "M. Takdenti"
    },
    {
      "name": "A. Sadr Hashemi Nejad"
    },
    {
      "name": "Z. Nouhi"
    },
    {
      "name": "S. St-Amand"
    },
    {
      "name": "C. Capdevielle"
    },
    {
      "name": "D. Issa"
    },
    {
      "name": "M. Riaud"
    },
    {
      "name": "A. A. N. Rose"
    },
    {
      "name": "M. Khacho"
    },
    {
      "name": "F. A. Mallette"
    },
    {
      "name": "M. Roffe"
    },
    {
      "name": "T. Alain"
    },
    {
      "name": "I. Topisirovic"
    },
    {
      "affs": [
        0
      ],
      "name": "L. Hulea"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fh8kt2914b21e.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.03.749206",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.03.749206v1.full",
  "id": "fh8kt2914b21e",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.03.749206v1",
  "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": "W7211939099",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.03.749206v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-03",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/fh8kt2914b21e.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:15Z",
      "native_id": "10.64898/2026.09.03.749206",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.03.749206v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma",
  "title_text": "eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:15Z",
  "url": "https://research.draconitic.com/paper/fh8kt2914b21e",
  "venue": "bioRxiv",
  "versions": []
}