{
  "abstract": "Background: CIC -rearranged sarcoma is a rare and highly aggressive cancer that primarily affects children and young adults and has few effective treatment options. Previous studies have identified molecular dependence on cyclin-dependent kinase 2 (CDK2), but additional therapeutic vulnerabilities remain poorly defined. Here, we investigate the activity of CDK2-targeted therapies and evaluate combination strategies using new patient-derived models of CIC -rearranged sarcoma.\n\nMethods: We established patient-derived cell lines and matching xenograft models from tumors harboring CIC::DUX4 and CIC::NUTM1 fusions, with xenograft studies performed in 7-week-old female NSG mice. We assessed the effects of CDK2 inhibition alone and in combination with cyclin-dependent kinase 9 (CDK9) inhibition using molecular, functional, and transcriptomic analyses in vitro and in vivo.\n\nResults: Here we show that CIC -rearranged sarcoma depends on the MYC oncogene and is vulnerable to CDK2 inhibition. The CDK2 inhibitor tagtociclib suppresses MYC-regulated gene expression, inhibits tumor cell proliferation, and reduces tumor growth in patient-derived models. Combined inhibition of CDK2 and CDK9 produces synergistic anti-tumor activity by further suppressing MYC-driven transcription, enhancing apoptotic cell death, and improving tumor control in vitro and in vivo.\n\nConclusions: These findings identify MYC-driven transcription as a therapeutic vulnerability in CIC -rearranged sarcoma and support combined CDK2 and CDK9 inhibition as a promising treatment strategy. The patient-derived models established in this study also provide valuable resources for future preclinical and translational research.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 24,
  "authors": [
    {
      "name": "Quentin Odom-Lewis"
    },
    {
      "name": "Samantha L. Davis"
    },
    {
      "name": "Stephan Pieper",
      "orcid": "0009-0009-2483-0379"
    },
    {
      "name": "Shannon M. R. Legge"
    },
    {
      "name": "Emilia F. A. Regenfuss"
    },
    {
      "name": "Nicolas Fernandez"
    },
    {
      "name": "Phillip D. Michaels"
    },
    {
      "name": "João A. Paulo",
      "orcid": "0000-0002-4291-413X"
    },
    {
      "name": "Steven P. Gygi",
      "orcid": "0000-0001-7626-0034"
    },
    {
      "name": "Chen Chu",
      "orcid": "0000-0001-8084-0867"
    },
    {
      "name": "Shanshan Zheng"
    },
    {
      "name": "Paola Dal Cin"
    },
    {
      "name": "Jason L. Hornick",
      "orcid": "0000-0001-6475-8345"
    },
    {
      "name": "Nicole L. Solimini",
      "orcid": "0009-0007-0002-0975"
    },
    {
      "name": "Timothy B. Branigan"
    },
    {
      "name": "Mohamed Alyousef"
    },
    {
      "name": "Emanuele Mazzola"
    },
    {
      "name": "Ewa T. Sicinska"
    },
    {
      "name": "Karen Bui",
      "orcid": "0000-0001-7582-853X"
    },
    {
      "name": "Prafulla C. Gokhale",
      "orcid": "0000-0002-1974-5921"
    },
    {
      "name": "Christopher A. French",
      "orcid": "0000-0002-7434-4987"
    },
    {
      "name": "George D. Demetri"
    },
    {
      "name": "Geoffrey I. Shapiro",
      "orcid": "0000-0002-3331-4095"
    },
    {
      "name": "Inga-Marie Schaefer",
      "orcid": "0000-0001-9710-5500"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2307fjtex0p49.bib",
  "cited_by": 0,
  "doi": "10.1038/s43856-026-01956-1",
  "fulltext_url": "https://europepmc.org/articles/PMC13728178",
  "id": "2307fjtex0p49",
  "issns": [
    "2730-664X"
  ],
  "landing_url": "https://www.nature.com/articles/s43856-026-01956-1",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2740|Sarcoma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7220861017",
  "pdf_url": "https://www.nature.com/articles/s43856-026-01956-1_reference.pdf",
  "pmcid": "PMC13728178",
  "pmid": "42972022",
  "published": "2026-10-07",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/2307fjtex0p49.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:53Z",
      "native_id": "10.1038/s43856-026-01956-1",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s43856-026-01956-1"
    },
    {
      "first_seen": "2026-11-04T15:20:44Z",
      "native_id": "MED:42972022",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42972022"
    },
    {
      "first_seen": "2026-11-06T12:23:54Z",
      "native_id": "PMC13728178",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s43856-026-01956-1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Sarcoma Diagnosis and Treatment",
      "subfield": "general"
    }
  ],
  "title": "Co-targeting CDK2 and CDK9 inhibits MYC oncogenic programs and has anti-tumor effects in CIC-rearranged sarcoma",
  "title_text": "Co-targeting CDK2 and CDK9 inhibits MYC oncogenic programs and has anti-tumor effects in CIC-rearranged sarcoma",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:23:54Z",
  "url": "https://research.draconitic.com/paper/2307fjtex0p49",
  "venue": "Communications Medicine",
  "versions": []
}