Inhibition of DNMT3B and PI3K/AKT/mTOR and ERK Pathways as a Novel Mechanism of Volasertib on Hypomethylating Agent-Resistant Cells
10.4062/biomolther.2022.117
- Author:
Eun-Ji CHOI
1
;
Bon-Kwan KOO
;
Eun-Hye HUR
;
Ju Hyun MOON
;
Ji Yun KIM
;
Han-Seung PARK
;
Yunsuk CHOI
;
Kyoo-Hyung LEE
;
Jung-Hee LEE
;
Eun Kyung CHOI
;
Je-Hwan LEE
Author Information
1. Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
- Publication Type:Original Article
- From:Biomolecules & Therapeutics
2023;31(3):319-329
- CountryRepublic of Korea
- Language:English
-
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.
