A multiscale pharmacokinetic-Boolean modelling framework for ibrutinib resistance in a Chronic Lymphocytic Leukaemia case study

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.