{
  "abstract": "Ibrutinib, a covalent Bruton's tyrosine kinase (BTK) inhibitor, achieves durable remissions in chronic lymphocytic leukaemia (CLL), and yet a substantial proportion of patients relapse. A fundamental question is how the quantitative dynamics of drug exposure relate to the regulatory programmes and cell fate decisions that characterise response and relapse. Addressing it requires a multiscale framework that bridges the quantitative pharmacology of drug exposure with the molecular mechanisms encoded in the gene regulatory network, a coupling that has remained largely unexplored in the context of targeted therapy resistance. Here we present a multi-scale computational framework that addresses this question by coupling continuous patient-specific pharmacokinetic profiles with discrete Boolean dynamics, bridging two modelling paradigms that have so far operated in isolation. Applied to a longitudinal single-cell dataset from one CLL patient treated with ibrutinib across three clinical timepoints (pre-treatment, response, relapse), the framework integrates gene regulatory network inference, cell fate trajectory analysis, and a stochastic Boolean model, whose dynamics is driven by the patient-specific monthly drug exposure. AP-1 and integrated stress response regulons were specific to relapse, and the coupled model reproduced the clinical course. Its perturbation screens identified co-inhibition of BTK with BCL2L1 or NFKB1 as synergistic, in line with the rationale for dual targeting of BTK and the BCL2 family in treatment-naive CLL. These results show how the framework turns single-patient data into mechanistic, testable hypotheses on resistance and combination therapy, which can be evaluated in larger cohorts and in experimental models.",
  "abstract_shown": true,
  "affiliations": [
    "Univ Toulouse, Oncopole Claudius Regaud, IUCT-Oncopole, Inserm, CRCT, Toulouse, France"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "M. Marku"
    },
    {
      "name": "C. Pineau"
    },
    {
      "name": "M. Hurtado"
    },
    {
      "name": "H. Chenel"
    },
    {
      "name": "J.-B. Woillard"
    },
    {
      "name": "L. Ysebaert"
    },
    {
      "name": "E. Chatelut"
    },
    {
      "name": "V. Pancaldi"
    },
    {
      "name": "M. White-Koning"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ameg6ykecnfj8.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.26.759125",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.759125v1.full",
  "id": "ameg6ykecnfj8",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.759125v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "systems biology"
    ],
    [
      "openalex",
      "2716|Chronic Lymphocytic Leukemia Research"
    ]
  ],
  "openalex": "W7224131728",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.759125v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/ameg6ykecnfj8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:30:00Z",
      "native_id": "10.64898/2026.10.26.759125",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.26.759125v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:systems biology",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "A multiscale pharmacokinetic-Boolean modelling framework for ibrutinib resistance in a Chronic Lymphocytic Leukaemia case study",
  "title_text": "A multiscale pharmacokinetic-Boolean modelling framework for ibrutinib resistance in a Chronic Lymphocytic Leukaemia case study",
  "type": "preprint",
  "updated_at": "2026-10-30T12:30:00Z",
  "url": "https://research.draconitic.com/paper/ameg6ykecnfj8",
  "venue": "bioRxiv",
  "versions": []
}