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

In a longitudinal single-cell dataset from one chronic lymphocytic leukaemia patient on ibrutinib, relapse-specific AP-1 and integrated stress response regulons were identified and the coupled model reproduced the clinical course.

• Why it matters: Relapse despite durable remissions raises a gap in linking quantitative drug exposure dynamics to gene-regulatory programmes and cell fate decisions underlying targeted therapy resistance.
• What they did: The study coupled patient-specific continuous pharmacokinetic profiles with discrete Boolean gene regulatory network dynamics, driven by monthly drug exposure across three timepoints (pre-treatment, response, relapse).
• The result: Perturbation screens predicted that co-inhibition of BTK with BCL2L1 or NFKB1 is synergistic, yielding mechanistic, testable hypotheses for resistance and combination therapy.