Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.117
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: gracehur@amc.seoul.kr (Hur EH), jhlee3@amc.seoul.kr (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.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
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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