Oncotarget

Research Papers:

Identification of volasertib-resistant mechanism and evaluation of combination effects with volasertib and other agents on acute myeloid leukemia

Yoshiya Adachi, Yuichi Ishikawa _ and Hitoshi Kiyoi

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Oncotarget. 2017; 8:78452-78465. https://doi.org/10.18632/oncotarget.19632

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Abstract

Yoshiya Adachi1, Yuichi Ishikawa1 and Hitoshi Kiyoi1

1Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

Correspondence to:

Yuichi Ishikawa, email: yishikaw@med.nagoya-u.ac.jp

Keywords: AML, PLK1 inhibitor, volasertib, resistance, MDR1

Received: March 06, 2017    Accepted: July 03, 2017    Published: July 26, 2017

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.


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