Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Inhibition of DNMT3B and PI3K/AKT/mTOR and ERK Pathways as a Novel Mechanism of Volasertib on Hypomethylating Agent-Resistant Cells

  • Eun-Ji Choi (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Bon-Kwan Koo (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Eun-Hye Hur (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Ju Hyun Moon (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Ji Yun Kim (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Han-Seung Park (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yunsuk Choi (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kyoo-Hyung Lee (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Jung-Hee Lee (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Eun Kyung Choi (Asan Preclinical Evaluation Center for Cancer Therapeutics, Asan Medical Center) ;
  • Je-Hwan Lee (Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2022.09.02
  • Accepted : 2022.10.26
  • Published : 2023.05.01
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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

Acknowledgement

This research was supported by a grant of the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (Grant number: 2021IP0076) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI15C0972).

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