Bruton’s Tyrosine Kinase Inhibitors Ibrutinib and Acalabrutinib Counteract Anthracycline Resistance in Cancer Cells Expressing AKR1C3

SIMPLE SUMMARY: The enzyme aldo-keto reductase 1C3 (AKR1C3) is present in several cancers, in which it is capable of actively metabolising different chemotherapy drugs and decreasing their cytotoxic effects. Therefore, the combination with specific inhibitors of AKR1C3 might prevent drug metabolism and increase its efficacy. We investigated the ability of Bruton’s tyrosine kinase inhibitors ibrutinib and acalabrutinib to block the AKR1C3 mediated inactivation of the anthracycline daunorubicin. Experimentation with recombinant AKR1C3 and different cancer cells expressing this enzyme outlined BTK-inhibitors as potential partners to synergise daunorubicin cytotoxicity in vitro. This evidence could be useful to improve the clinical outcome of anthracycline-based chemotherapies. ABSTRACT: Over the last few years, aldo-keto reductase family 1 member C3 (AKR1C3) has been associated with the emergence of multidrug resistance (MDR), thereby hindering chemotherapy against cancer. In particular, impaired efficacy of the gold standards of induction therapy in acute myeloid leukaemia (AML) has been correlated with AKR1C3 expression, as this enzyme metabolises several drugs including anthracyclines. Therefore, the development of selective AKR1C3 inhibitors may help to overcome chemoresistance in clinical practice. In this regard, we demonstrated that Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib efficiently prevented daunorubicin (Dau) inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in cancer cells. This revealed a synergistic effect of BTK inhibitors on Dau cytotoxicity in cancer cells expressing AKR1C3 both exogenously and endogenously, thus reverting anthracycline resistance in vitro. These findings suggest that BTK inhibitors have a novel off-target action, which can be exploited against leukaemia through combination regimens with standard chemotherapeutics like anthracyclines.