Biomolecules & Therapeutics
Inhibition of DNMT3B and PI3K/AKT/mTOR and ERK Pathways as a Novel Mechanism of Volasertib on Hypomethylating Agent-Resistant Cells
Eun-Ji Choi1,†, Bon-Kwan Koo1,†, Eun-Hye Hur1,*, Ju Hyun Moon1, Ji Yun Kim1, Han-Seung Park1, Yunsuk Choi1, Kyoo-Hyung Lee1, Jung-Hee Lee1, Eun Kyung Choi2 and Je-Hwan Lee1,*
1Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505,
2Asan Preclinical Evaluation Center for Cancer Therapeutics, Asan Medical Center, Seoul 05505, Republic of Korea
*E-mail: (Hur EH), (Lee JH)
Tel: +82-2-3010-4140 (Hur EH), +82-2-3010-3218 (Lee JH)
The first two authors contributed equally to this work.
Received: September 2, 2022; Revised: October 25, 2022; Accepted: October 26, 2022; Published online: November 16, 2022.
© The Korean Society of Applied Pharmacology. All rights reserved.

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Resistance to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is a concerning problem. Polo-like kinase 1 (PLK1) is a key cell cycle modulator and is known to be associated with an activation of the PI3K pathway, which is related to the stabilization of DNA methyltransferase 1 (DNMT1), a target of HMAs. We investigated the effects of volasertib on HMA-resistant cell lines (MOLM/AZA-1 and MOLM/DEC-5) derived from MOLM-13, and bone marrow (BM) samples obtained from patients with MDS (BM blasts >5%) or AML evolved from MDS (MDS/AML). Volasertib effectively inhibited the proliferation of HMA-resistant cells with suppression of DNMTs and PI3K/AKT/mTOR and ERK pathways. Volasertib also showed significant inhibitory effects against primary BM cells from patients with MDS or MDS/AML, and the effects of volasertib inversely correlated with DNMT3B expression. The DNMT3B-overexpressed AML cells showed primary resistance to volasertib treatment. Our data suggest that volasertib has a potential role in overcoming HMA resistance in patients with MDS and MDS/ AML by suppressing the expression of DNMT3 enzymes and PI3K/AKT/mTOR and ERK pathways. We also found that DNMT3B overexpression might be associated with resistance to volasertib.
Keywords: Volasertib, Hypomethylating agent-resistance, DNA methyltransferase, PI3K/AKT/mTOR, ERK pathway

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