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A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia
FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Multiple FLT3 inhibitors are in various stages of clinical evaluation. However, resistance to FLT3 inhibitors resulting from acquired point mutations in tyros...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255005/ https://www.ncbi.nlm.nih.gov/pubmed/34217323 http://dx.doi.org/10.1186/s13045-021-01098-y |
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author | Wang, Peihong Xiao, Xinhua Zhang, Yuyin Zhang, Baoyuan Li, Donghe Liu, Mingzhu Xie, Xi Liu, Chenxuan Liu, Ping Ren, Ruibao |
author_facet | Wang, Peihong Xiao, Xinhua Zhang, Yuyin Zhang, Baoyuan Li, Donghe Liu, Mingzhu Xie, Xi Liu, Chenxuan Liu, Ping Ren, Ruibao |
author_sort | Wang, Peihong |
collection | PubMed |
description | FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Multiple FLT3 inhibitors are in various stages of clinical evaluation. However, resistance to FLT3 inhibitors resulting from acquired point mutations in tyrosine kinase domain (TKD) have limited the sustained efficacy of treatments, and a “gatekeeper” mutation (F691L) is resistant to most available FLT3 inhibitors. Thus, new FLT3 inhibitors against both FLT3 internal tandem duplication (FLT3-ITD) and FLT3-TKD mutations (including F691L) are urgently sought. Herein, we identified KX2-391 as a dual FLT3 and tubulin inhibitor and investigated its efficacy and mechanisms in overcoming drug-resistant FLT3-ITD-TKD mutations in AML. KX2-391 exhibited potent growth inhibitory and apoptosis promoting effects on diverse AML cell lines harboring FLT3-ITD mutations and AC220-resistant mutations at the D835 and F691 residues in TKD and inhibited FLT3 phosphorylation and its downstream signaling targets. Orally administered KX2-391 significantly prolonged the survival of a murine leukemia model induced by FLT3-ITD-F691L. KX2-391 also significantly inhibited the growth of 4 primary AML cells expressing FLT3-ITD and 2 primary AML cells expressing FLT3-ITD-D835Y. Our preclinical data highlight KX2-391 as a promising FLT3 inhibitor for the treatment of AML patients harboring FLT3 mutations, especially refractory/relapsed patients with F691L and other FLT3-TKD mutations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-021-01098-y. |
format | Online Article Text |
id | pubmed-8255005 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-82550052021-07-06 A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia Wang, Peihong Xiao, Xinhua Zhang, Yuyin Zhang, Baoyuan Li, Donghe Liu, Mingzhu Xie, Xi Liu, Chenxuan Liu, Ping Ren, Ruibao J Hematol Oncol Letter to the Editor FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Multiple FLT3 inhibitors are in various stages of clinical evaluation. However, resistance to FLT3 inhibitors resulting from acquired point mutations in tyrosine kinase domain (TKD) have limited the sustained efficacy of treatments, and a “gatekeeper” mutation (F691L) is resistant to most available FLT3 inhibitors. Thus, new FLT3 inhibitors against both FLT3 internal tandem duplication (FLT3-ITD) and FLT3-TKD mutations (including F691L) are urgently sought. Herein, we identified KX2-391 as a dual FLT3 and tubulin inhibitor and investigated its efficacy and mechanisms in overcoming drug-resistant FLT3-ITD-TKD mutations in AML. KX2-391 exhibited potent growth inhibitory and apoptosis promoting effects on diverse AML cell lines harboring FLT3-ITD mutations and AC220-resistant mutations at the D835 and F691 residues in TKD and inhibited FLT3 phosphorylation and its downstream signaling targets. Orally administered KX2-391 significantly prolonged the survival of a murine leukemia model induced by FLT3-ITD-F691L. KX2-391 also significantly inhibited the growth of 4 primary AML cells expressing FLT3-ITD and 2 primary AML cells expressing FLT3-ITD-D835Y. Our preclinical data highlight KX2-391 as a promising FLT3 inhibitor for the treatment of AML patients harboring FLT3 mutations, especially refractory/relapsed patients with F691L and other FLT3-TKD mutations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-021-01098-y. BioMed Central 2021-07-03 /pmc/articles/PMC8255005/ /pubmed/34217323 http://dx.doi.org/10.1186/s13045-021-01098-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Letter to the Editor Wang, Peihong Xiao, Xinhua Zhang, Yuyin Zhang, Baoyuan Li, Donghe Liu, Mingzhu Xie, Xi Liu, Chenxuan Liu, Ping Ren, Ruibao A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia |
title | A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia |
title_full | A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia |
title_fullStr | A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia |
title_full_unstemmed | A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia |
title_short | A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia |
title_sort | dual inhibitor overcomes drug-resistant flt3-itd acute myeloid leukemia |
topic | Letter to the Editor |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255005/ https://www.ncbi.nlm.nih.gov/pubmed/34217323 http://dx.doi.org/10.1186/s13045-021-01098-y |
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