{
  "abstract": "Background: Metastatic colorectal cancer (mCRC) remains a significant clinical challenge due to the emergence of drug resistance, highlighting the need for new therapeutic strategies. Aberrant regulation of the proteome drives cancer progression, and dissecting these alterations offers opportunities for targeted intervention. We aimed to identify candidate kinase dependencies in mCRC and to test a rational combination strategy in patient-derived models.\n\nMethods: We performed proteomic and phosphoproteomic profiling of 10 mCRC tissues, their matched patient-derived organoids (PDOs) and normal colon mucosa, integrated with whole-exome sequencing. Kinase activities were inferred by kinase-substrate enrichment analysis. Silmitasertib-mediated casein kinase II (CKII) inhibition, alone and combined with the MEK inhibitor trametinib, was evaluated by ex vivo drug screening, western blot, flow cytometry and drug-interaction analysis across the PDO cohort and in normal colon PDOs.\n\nResults: PDOs recapitulated the molecular features of matched tumours. Both tissues and PDOs showed consistently elevated CKII activity. Silmitasertib exerted heterogeneous antitumour activity, and resistance was associated with MAPK and Akt-mTOR signalling activity. Combining silmitasertib with trametinib produced an additive reduction of both resistance-associated pathways with little effect on the viability of normal colon PDOs. The combination also significantly reduced CKII activity, the abundance of active β-catenin and the colorectal cancer stem cell pool.\n\nConclusions: Phosphoproteomic profiling identified CKII as a therapeutic vulnerability in mCRC and provided a rationale for combining silmitasertib with MEK inhibition, offering a candidate combination strategy for mCRC.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40164-026-00855-4.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland",
    "Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CG Utrecht, The Netherlands",
    "Oncode Institute, Utrecht, The Netherlands",
    "IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, Milan, 20089 Italy",
    "Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland",
    "Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland",
    "Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy",
    "Faculty of Medicine, University of Basel, Klingelbergstrasse 61, Basel, 4056 Switzerland",
    "Department of Visceral Surgery, Clarunis, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland",
    "Kantonsspital Baselland, Liestal, 4410 Switzerland"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
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        0,
        1,
        2
      ],
      "name": "Mattia Marinucci"
    },
    {
      "affs": [
        3
      ],
      "name": "Federico Donà"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Gina F. Boot"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Cinzia Esposito"
    },
    {
      "affs": [
        4
      ],
      "name": "Elenia Toccafondi"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Daniela Liberati"
    },
    {
      "affs": [
        5
      ],
      "name": "Andrej Benjak"
    },
    {
      "affs": [
        4
      ],
      "name": "Lara Zaidi"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Melania Lazzari"
    },
    {
      "affs": [
        3
      ],
      "name": "Giulia Milardi"
    },
    {
      "affs": [
        0
      ],
      "name": "Karolina Guja-Jarosz"
    },
    {
      "affs": [
        3
      ],
      "name": "Miriam Cieri"
    },
    {
      "affs": [
        4
      ],
      "name": "Huiche Feng"
    },
    {
      "affs": [
        0
      ],
      "name": "Mairene Coto-Llerena"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Raoul A. Droeser"
    },
    {
      "affs": [
        8
      ],
      "name": "Savas D. Soysal"
    },
    {
      "affs": [
        9
      ],
      "name": "Otto Kollmar"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Guido Torzilli"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Antonino Spinelli"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Luigi M. Terracciano"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Charlotte K. Y. Ng"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Salvatore Piscuoglio",
      "orcid": "0000-0003-2686-2939"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dx9b2n1pv3j0n.bib",
  "cited_by": 0,
  "doi": "10.1186/s40164-026-00855-4",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13737822/",
  "id": "dx9b2n1pv3j0n",
  "issns": [
    "2162-3619"
  ],
  "landing_url": "https://doi.org/10.1186/s40164-026-00855-4",
  "language": "en",
  "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",
      "Research"
    ],
    [
      "openalex",
      "2730|Colorectal Cancer Treatments and Studies"
    ]
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  "openalex": "W7225314036",
  "pdf_url": null,
  "pmcid": "PMC13737822",
  "pmid": "42989420",
  "published": "2026-11-05",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/dx9b2n1pv3j0n.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:22:55Z",
      "native_id": "PMC13737822",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s40164-026-00855-4"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Colorectal Cancer Treatments and Studies",
      "subfield": "oncology"
    }
  ],
  "title": "Combined casein kinase II and MAPK signalling inhibition as a therapeutic strategy for metastatic colorectal cancer",
  "title_text": "Combined casein kinase II and MAPK signalling inhibition as a therapeutic strategy for metastatic colorectal cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:55Z",
  "url": "https://research.draconitic.com/paper/dx9b2n1pv3j0n",
  "venue": "Experimental Hematology & Oncology",
  "versions": []
}