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https://doi.org/10.1371/journal.pone.0174107
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 imatinib pracinostat protein tyrosine kinase inhibitor antineoplastic agent BCR ABL protein benzimidazole derivative BIM protein enzyme inhibitor histone deacetylase inhibitor SB939 compound apoptosis Article BIM gene cancer resistance cell viability chronic myeloid leukemia controlled study DNA polymorphism drug efficacy drug mechanism drug sensitivity gene gene deletion human human cell leukemia cell RNA splicing antagonists and inhibitors chronic myeloid leukemia drug effects gene deletion genetics K-562 cell line pathology Antineoplastic Agents Apoptosis Bcl-2-Like Protein 11 Benzimidazoles Enzyme Inhibitors Fusion Proteins, bcr-abl Gene Deletion Histone Deacetylase Inhibitors Humans 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. https://doi.org/10.1371/journal.pone.0174107 | 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 | URI: | https://scholarbank.nus.edu.sg/handle/10635/166015 | ISSN: | 19326203 | DOI: | 10.1371/journal.pone.0174107 |
Appears in Collections: | Elements Staff Publications |
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