{
  "abstract": "Diffuse midline glioma is an epigenetically driven disease defined by alterations targeting the histone post-translational modification H3K27me3 resulting in epigenetic rewiring and imposing unique metabolic dependencies. ACVR1-mutations arise in ~25% of DMG H3K27-altered patients and impart a selective dependency on the kinase it encodes (ALK2), however ALK2 inhibitors show modest single-agent efficacy in vivo. In an attempt to better understand the cellular consequences of ALK2 inhibition to identify mechanistically-driven drug combinations, integrated multi-omics analysis was performed and revealed a novel role for ALK2 in cholesterol homeostasis while CRISPR and high-throughput drug screens identified hits targeting cholesterol metabolism as sensitisers to ALK2i. In vivo assessment of ALK2i plus clinically well-tolerated statins revealed a significant increase in the median survival compared to vehicle. Forced differentiation of DMG cells from an oligodendrocyte precursor-like to an astrocyte-like cell-state and led to a significant decrease in ALK2i sensitivity and synergy with statins, which was phenocopied when DMG cells were co-cultured with normal astrocytes. We identify a previously unappreciated role for ALK2 signalling in cholesterol homeostasis, showing cell-state dependency, and identify a rational combinatorial strategy for clinical translation.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Cancer Research"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 24,
  "authors": [
    {
      "name": "R. Rogers"
    },
    {
      "name": "Y. Grabovska"
    },
    {
      "name": "A. Mackay"
    },
    {
      "name": "D. Carvalho"
    },
    {
      "name": "C. Dobinson"
    },
    {
      "name": "R. Pereira"
    },
    {
      "name": "A. Burford"
    },
    {
      "name": "L. Bevington"
    },
    {
      "name": "V. Molinari"
    },
    {
      "name": "J. Song"
    },
    {
      "name": "H. Tari"
    },
    {
      "name": "R. Ruddle"
    },
    {
      "name": "J. Nkrumah"
    },
    {
      "name": "D. Sejdiu"
    },
    {
      "name": "N. Chew"
    },
    {
      "name": "V. Tsui"
    },
    {
      "name": "C. Sun"
    },
    {
      "name": "M. Vinci"
    },
    {
      "name": "G. Pericoli"
    },
    {
      "name": "O. Becher"
    },
    {
      "name": "J. Fortin"
    },
    {
      "name": "P. Sampson"
    },
    {
      "name": "R. Firestein"
    },
    {
      "affs": [
        0
      ],
      "name": "C. Jones"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dm48djpb1zf1d.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.23.753440",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.23.753440v1.full",
  "id": "dm48djpb1zf1d",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.23.753440v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2716|Glioma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7214082918",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.23.753440v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-23",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dm48djpb1zf1d.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:06Z",
      "native_id": "10.64898/2026.09.23.753440",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.23.753440v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Combination of ALK2 and cholesterol targeting agents exploits linked genetic and metabolic dependencies in diffuse midline glioma",
  "title_text": "Combination of ALK2 and cholesterol targeting agents exploits linked genetic and metabolic dependencies in diffuse midline glioma",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:06Z",
  "url": "https://research.draconitic.com/paper/dm48djpb1zf1d",
  "venue": "bioRxiv",
  "versions": []
}