Dasatinib is a second-generation breakpoint cluster region-abelson 1 (BCR::ABL1) tyrosine kinase inhibitor (TKI) used for the treatment of chronic myeloid leukemia (CML). Overexpression of ATP-binding cassette subfamily G member 2 (ABCG2) in CML cells contributes to dasatinib resistance and poor chemotherapeutic responses. Considering that the xanthine oxidase inhibitor febuxostat has anti-ABCG2 activity, febuxostat may enhance the efficacy of dasatinib. However, the mechanism of action of febuxostat and its effects on the efficacy and safety of dasatinib in patients with CML are unknown. Therefore, this study aimed to retrospectively investigate the clinical impact of concomitant febuxostat on the efficacy of dasatinib in 65 patients with CML. Moreover, its underlying mechanism was explored in vitro using an ABCG2-overexpressing CML cell line (K562-ABCG2 cells). The retrospective study revealed that the achievement ratios of early molecular response at three months and major molecular response at 12 months after dasatinib treatment in patients with febuxostat were significantly higher than those in patients without febuxostat (91 % vs. 70 %, p = 0.034, 86 % vs. 53 %, p = 0.013, respectively). In vitro studies showed that febuxostat significantly decreased cell viability and increased the residual dasatinib concentration in dasatinib-treated K562-ABCG2 cells. Moreover, phosphorylated BCR::ABL1 levels in dasatinib-treated K562-ABCG2 cells were significantly decreased by febuxostat. Overall, concomitant febuxostat enhanced the efficacy of dasatinib in patients with CML. This was achieved partially by inhibition of ABCG2-mediated excretion of dasatinib from CML cells. Therefore, these findings provide important insights for improving CML treatment and overcoming TKI resistance.
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http://dx.doi.org/10.1016/j.biopha.2024.117709 | DOI Listing |
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