Abstract
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.
Highlights
The polo-like kinase (PLK) family are serine/ threonine protein kinases and consist of five members: PLK1, PLK2, PLK3, PLK4 and PLK5 [1,2,3]
To examine the efficacy of volasertib, we evaluated GI50 values of volasertib in a variety of human acute myeloid leukemia (AML), chronic myeloid leukemia in blast crisis (CML-BC), acute lymphoblastic leukemia (ALL), malignant lymphoma (ML) and multiple myeloma (MM) cell lines
The expression levels of PLK2 and PLK3 mRNA were quite lower than those of PLK1 mRNA in the AML cell lines (Supplementary Figure 1C) and there were no significant correlations between the PLK2 and PLK3 mRNA expression levels, and the resistance to volasertib
Summary
The polo-like kinase (PLK) family are serine/ threonine protein kinases and consist of five members: PLK1, PLK2, PLK3, PLK4 and PLK5 [1,2,3] These PLKs regulate many steps of the cell cycle, centriole duplication, DNA replication, centrosome separation, maturation, mitotic entry, spindle formation, chromosome segregation and cytokinesis. Volasertib is an ATP-competitive PLK inhibitor and potently inhibits PLK1, PLK2 and PLK3 with IC50 values of 0.87 nM, 5 nM and 56 nM, respectively [8]. It does not exhibit any inhibitory effects against a panel of more than 50 other kinases at concentrations up to 10 μM. Volasertib was clinically efficient in several cancers and prominent in the clinical trials against AML patients [11]
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