Repurposing primaquine diphosphate for imatinib-resistant chronic myeloid leukemia via targeting BCR-ABL and Wnt/β-catenin pathway.

Chronic myeloid leukemia (CML) is defined by the Philadelphia chromosome-derived BCR::ABL1 fusion gene. Imatinib, a first-line treatment targeting the BCR-ABL protein, has markedly improved clinical outcomes in patients with BCR::ABL1 + CML. However, drug resistance remains a critical therapeutic challenge in the management of CML. In this study, we uncovered that low concentrations of antimalarial drug primaquine diphosphate (PRQ) induced the differentiation of imatinib-resistant CML cells, while high concentrations triggered their apoptosis. Mechanistically, PRQ inhibited the Wnt/β-catenin pathway and promoted the degradation of both wild-type and multiple imatinib-resistant BCR::ABL1 mutants. Furthermore, PRQ effectively induced differentiation, inhibited colony formation of primary CML blasts, and suppressed the neoplastic growth of imatinib-resistant CML cells in a murine xenograft model. These findings suggest that the antimalarial drug PRQ may have potential for overcoming imatinib resistance in CML, warranting further evaluation as a repurposed candidate.