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A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors
FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia and a target for tyrosine kinase inhibitors (TKI). FLT3 TKIs have yielded limited improvements to clinical outcomes. One reason for this is TKI inhibition by endogenous factors. We characterized plasma pr...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478262/ https://www.ncbi.nlm.nih.gov/pubmed/34589716 http://dx.doi.org/10.1158/2643-3230.BCD-20-0119 |
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author | Young, David J. Nguyen, Bao Li, Li Higashimoto, Tomoyasu Levis, Mark J. Liu, Jun O. Small, Donald |
author_facet | Young, David J. Nguyen, Bao Li, Li Higashimoto, Tomoyasu Levis, Mark J. Liu, Jun O. Small, Donald |
author_sort | Young, David J. |
collection | PubMed |
description | FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia and a target for tyrosine kinase inhibitors (TKI). FLT3 TKIs have yielded limited improvements to clinical outcomes. One reason for this is TKI inhibition by endogenous factors. We characterized plasma protein binding of FLT3 TKI, specifically staurosporine derivatives (STS-TKI) by alpha-1-acid glycoprotein (AGP), simulating its effects upon drug efficacy. Human AGP inhibits the antiproliferative activity of STS-TKI in FLT3/ITD-dependent cells, with IC(50) shifts higher than clinically achievable. This is not seen with nonhuman plasma. Mifepristone cotreatment, with its higher AGP affinity, improves TKI activity despite AGP, yielding IC(50)s predicted to be clinically effective. In a mouse model of AGP drug inhibition, mifepristone restores midostaurin activity. This suggests combinatorial methods for overcoming plasma protein inhibition of existing TKIs for leukemia as well as providing a platform for investigating the drug–protein interaction space for developing more potent small-molecule agents. SIGNIFICANCE: Our data provide a mechanism for the failure of some previous TKI clinical trials. The ability of mifepristone to disinhibit TKIs suggests an approach by which the combination of TKIs with already approved and well-tolerated drugs may restore TKI activity. |
format | Online Article Text |
id | pubmed-8478262 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-84782622021-09-28 A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors Young, David J. Nguyen, Bao Li, Li Higashimoto, Tomoyasu Levis, Mark J. Liu, Jun O. Small, Donald Blood Cancer Discov Research Articles FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia and a target for tyrosine kinase inhibitors (TKI). FLT3 TKIs have yielded limited improvements to clinical outcomes. One reason for this is TKI inhibition by endogenous factors. We characterized plasma protein binding of FLT3 TKI, specifically staurosporine derivatives (STS-TKI) by alpha-1-acid glycoprotein (AGP), simulating its effects upon drug efficacy. Human AGP inhibits the antiproliferative activity of STS-TKI in FLT3/ITD-dependent cells, with IC(50) shifts higher than clinically achievable. This is not seen with nonhuman plasma. Mifepristone cotreatment, with its higher AGP affinity, improves TKI activity despite AGP, yielding IC(50)s predicted to be clinically effective. In a mouse model of AGP drug inhibition, mifepristone restores midostaurin activity. This suggests combinatorial methods for overcoming plasma protein inhibition of existing TKIs for leukemia as well as providing a platform for investigating the drug–protein interaction space for developing more potent small-molecule agents. SIGNIFICANCE: Our data provide a mechanism for the failure of some previous TKI clinical trials. The ability of mifepristone to disinhibit TKIs suggests an approach by which the combination of TKIs with already approved and well-tolerated drugs may restore TKI activity. American Association for Cancer Research 2021-07-02 /pmc/articles/PMC8478262/ /pubmed/34589716 http://dx.doi.org/10.1158/2643-3230.BCD-20-0119 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs International 4.0 License. |
spellingShingle | Research Articles Young, David J. Nguyen, Bao Li, Li Higashimoto, Tomoyasu Levis, Mark J. Liu, Jun O. Small, Donald A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors |
title | A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors |
title_full | A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors |
title_fullStr | A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors |
title_full_unstemmed | A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors |
title_short | A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors |
title_sort | method for overcoming plasma protein inhibition of tyrosine kinase inhibitors |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478262/ https://www.ncbi.nlm.nih.gov/pubmed/34589716 http://dx.doi.org/10.1158/2643-3230.BCD-20-0119 |
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