Volasertib, a selective PLK1 inhibitor, was effective for
acute myeloid leukemia (AML) patients in clinical trials. However, its efficacy was limited in mono-
therapy, and a higher incidence of fatal events was revealed in the combination with low-dose
cytarabine. Thus, optimization of combination
therapy with
volasertib and other agents is necessary for its clinical development, and the predictive factors for response or resistance to
volasertib remain largely unknown. In this study, we investigated the resistance mechanism in
volasertib-resistant cell lines and the combination effects with other agents, such as
azacitidine (AZA), on AML cells. We identified that mutations in the
ATP-binding domain of PLK1 and expression of MDR1 conferred resistance to
volasertib. In the combination
therapy, the effects of AZA differed among cells, but were prominent in the cells with higher GI50 values of
volasertib in mono-
therapy. Furthermore, we identified that the cells in G2/M phase were more sensitive to
volasertib, and the PI3K/AKT pathway was up-regulated upon administration of
volasertib. Combination
therapies with the agents that caused cell cycle accumulation in G2/M phase or with PI3K inhibitor were highly potent against AML cells. Our findings provide strategies for further clinical development of
volasertib and PLK inhibitors for AML.