Tirabrutinib–anthracycline interactions in the brain tumor microenvironment: a focus on metabolic inactivation and resistance

Anthracyclines (ANTs) remain essential in many anticancer regimens, yet their clinical utility is often limited by multidrug resistance. Recent studies suggest that Bruton’s tyrosine kinase inhibitors (BTKis) may enhance the efficacy of ANT-based therapies, including those targeting brain tumors. This study investigates how tirabrutinib may contribute to such enhancement via interactions with aldo-keto reductase 1C3 (AKR1C3) and ABC efflux transporters. Research design and methods: The inhibitory potential of tirabrutinib was evaluated using recombinant enzymes, transiently transfected HCT116 cells, and cell lines with differential AKR1C3 expression (T98G, MRC-5). ABC transporter-expressing cells were used to assess daunorubicin accumulation. Western blotting was used to examine whether tirabrutinib alters AKR1C3 protein expression. Results: Tirabrutinib inhibited daunorubicin metabolism in both recombinant AKR1C3 assays and AKR1C3-expressing cells, but had no effect in non-expressing cells. It also enhanced intracellular accumulation of daunorubicin in relevant models. No significant changes in AKR1C3 expression were observed following tirabrutinib treatment. Conclusions: Our in vitro data demonstrate that tirabrutinib influences daunorubicin pharmacodynamics by targeting both metabolic and transport pathways. However, Chou-Talalay analysis highlights the importance of appropriate dosing to achieve therapeutic synergy in combination regimens.