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Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms

FLT3-ITD mutations occur in 20–30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2(nd) generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenv...

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Autores principales: Patel, Ami B., Pomicter, Anthony D., Yan, Dongqing, Eiring, Anna M., Antelope, Orlando, Schumacher, Jonathan A., Kelley, Todd W., Tantravahi, Srinivas K., Kovacsovics, Tibor J., Shami, Paul J., O’Hare, Thomas, Deininger, Michael W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606260/
https://www.ncbi.nlm.nih.gov/pubmed/32409689
http://dx.doi.org/10.1038/s41375-020-0858-1
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author Patel, Ami B.
Pomicter, Anthony D.
Yan, Dongqing
Eiring, Anna M.
Antelope, Orlando
Schumacher, Jonathan A.
Kelley, Todd W.
Tantravahi, Srinivas K.
Kovacsovics, Tibor J.
Shami, Paul J.
O’Hare, Thomas
Deininger, Michael W.
author_facet Patel, Ami B.
Pomicter, Anthony D.
Yan, Dongqing
Eiring, Anna M.
Antelope, Orlando
Schumacher, Jonathan A.
Kelley, Todd W.
Tantravahi, Srinivas K.
Kovacsovics, Tibor J.
Shami, Paul J.
O’Hare, Thomas
Deininger, Michael W.
author_sort Patel, Ami B.
collection PubMed
description FLT3-ITD mutations occur in 20–30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2(nd) generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenvironment facilitates leukemia cell survival despite continued on-target inhibition. We demonstrate that human bone marrow derived conditioned medium (CM) protects FLT3-ITD(+) AML cells from the 2(nd) generation FLT3 TKI quizartinib and activates STAT3 and STAT5 in leukemia cells. Extrinsic activation of STAT5 by CM is the primary mediator of leukemia cell resistance to FLT3 inhibition. Combination treatment with quizartinib and dasatinib abolishes STAT5 activation and significantly reduces the IC(50) of quizartinib in FLT3-ITD(+) AML cells cultured in CM. We demonstrate that CM protects FLT3-ITD(+) AML cells from the inhibitory effects of quizartinib on glycolysis and that this is partially reversed by treating cells with the combination of quizartinib and dasatinib. Using a doxycycline-inducible STAT5 knockdown in the FLT3-ITD(+) MOLM-13 cell line, we show that dasatinib-mediated suppression of leukemia cell glycolytic activity is STAT5-independent and provide a preclinical rationale for combination treatment with quizartinib and dasatinib in FLT3-ITD(+) AML.
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spelling pubmed-76062602020-11-14 Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms Patel, Ami B. Pomicter, Anthony D. Yan, Dongqing Eiring, Anna M. Antelope, Orlando Schumacher, Jonathan A. Kelley, Todd W. Tantravahi, Srinivas K. Kovacsovics, Tibor J. Shami, Paul J. O’Hare, Thomas Deininger, Michael W. Leukemia Article FLT3-ITD mutations occur in 20–30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2(nd) generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenvironment facilitates leukemia cell survival despite continued on-target inhibition. We demonstrate that human bone marrow derived conditioned medium (CM) protects FLT3-ITD(+) AML cells from the 2(nd) generation FLT3 TKI quizartinib and activates STAT3 and STAT5 in leukemia cells. Extrinsic activation of STAT5 by CM is the primary mediator of leukemia cell resistance to FLT3 inhibition. Combination treatment with quizartinib and dasatinib abolishes STAT5 activation and significantly reduces the IC(50) of quizartinib in FLT3-ITD(+) AML cells cultured in CM. We demonstrate that CM protects FLT3-ITD(+) AML cells from the inhibitory effects of quizartinib on glycolysis and that this is partially reversed by treating cells with the combination of quizartinib and dasatinib. Using a doxycycline-inducible STAT5 knockdown in the FLT3-ITD(+) MOLM-13 cell line, we show that dasatinib-mediated suppression of leukemia cell glycolytic activity is STAT5-independent and provide a preclinical rationale for combination treatment with quizartinib and dasatinib in FLT3-ITD(+) AML. 2020-05-14 2020-11 /pmc/articles/PMC7606260/ /pubmed/32409689 http://dx.doi.org/10.1038/s41375-020-0858-1 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Patel, Ami B.
Pomicter, Anthony D.
Yan, Dongqing
Eiring, Anna M.
Antelope, Orlando
Schumacher, Jonathan A.
Kelley, Todd W.
Tantravahi, Srinivas K.
Kovacsovics, Tibor J.
Shami, Paul J.
O’Hare, Thomas
Deininger, Michael W.
Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms
title Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms
title_full Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms
title_fullStr Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms
title_full_unstemmed Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms
title_short Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms
title_sort dasatinib overcomes stroma-based resistance to the flt3 inhibitor quizartinib using multiple mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606260/
https://www.ncbi.nlm.nih.gov/pubmed/32409689
http://dx.doi.org/10.1038/s41375-020-0858-1
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