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Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia

BACKGROUND: Acute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops qu...

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Autores principales: Yang, Jingmei, Friedman, Ran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416533/
https://www.ncbi.nlm.nih.gov/pubmed/37568211
http://dx.doi.org/10.1186/s12935-023-03000-x
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author Yang, Jingmei
Friedman, Ran
author_facet Yang, Jingmei
Friedman, Ran
author_sort Yang, Jingmei
collection PubMed
description BACKGROUND: Acute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly. METHODS: We examined combination therapies aimed at FLT3(+)-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism. RESULTS: We show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance. CONCLUSIONS: This study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-023-03000-x.
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spelling pubmed-104165332023-08-12 Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia Yang, Jingmei Friedman, Ran Cancer Cell Int Research BACKGROUND: Acute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly. METHODS: We examined combination therapies aimed at FLT3(+)-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism. RESULTS: We show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance. CONCLUSIONS: This study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-023-03000-x. BioMed Central 2023-08-11 /pmc/articles/PMC10416533/ /pubmed/37568211 http://dx.doi.org/10.1186/s12935-023-03000-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 Research
Yang, Jingmei
Friedman, Ran
Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia
title Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia
title_full Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia
title_fullStr Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia
title_full_unstemmed Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia
title_short Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia
title_sort combination strategies to overcome drug resistance in flt(+) acute myeloid leukaemia
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10416533/
https://www.ncbi.nlm.nih.gov/pubmed/37568211
http://dx.doi.org/10.1186/s12935-023-03000-x
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