Identification of volasertib-resistant mechanism and evaluation of combination effects with volasertib and other agents on acute myeloid leukemia
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Yoshiya Adachi1, Yuichi Ishikawa1 and Hitoshi Kiyoi1
1Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Yuichi Ishikawa, email: [email protected]
Keywords: AML, PLK1 inhibitor, volasertib, resistance, MDR1
Received: March 06, 2017 Accepted: July 03, 2017 Published: July 26, 2017
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.
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