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Title: The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia
Authors: Rauzan M. 
Chuah C.T.H. 
Ko T.K. 
Tiong Ong S. 
Keywords: BCR ABL protein
BIM protein
protein tyrosine kinase inhibitor
antineoplastic agent
BCR ABL protein
benzimidazole derivative
BIM protein
enzyme inhibitor
histone deacetylase inhibitor
SB939 compound
BIM gene
cancer resistance
cell viability
chronic myeloid leukemia
controlled study
DNA polymorphism
drug efficacy
drug mechanism
drug sensitivity
gene deletion
human cell
leukemia cell
RNA splicing
antagonists and inhibitors
chronic myeloid leukemia
drug effects
gene deletion
K-562 cell line
Antineoplastic Agents
Bcl-2-Like Protein 11
Enzyme Inhibitors
Fusion Proteins, bcr-abl
Gene Deletion
Histone Deacetylase Inhibitors
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
RNA Splicing
Issue Date: 2017
Publisher: Public Library of Science
Citation: Rauzan M., Chuah C.T.H., Ko T.K., Tiong Ong S. (2017). The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia. PLoS ONE 12 (3) : e0174107. ScholarBank@NUS Repository.
Abstract: Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletionassociated TKI resistance. © 2017 Rauzan et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
ISSN: 19326203
DOI: 10.1371/journal.pone.0174107
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