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Resistance to targeted therapies in acute myeloid leukemia
The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or sec...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898349/ https://www.ncbi.nlm.nih.gov/pubmed/36318439 http://dx.doi.org/10.1007/s10585-022-10189-0 |
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author | Mecklenbrauck, Rabea Heuser, Michael |
author_facet | Mecklenbrauck, Rabea Heuser, Michael |
author_sort | Mecklenbrauck, Rabea |
collection | PubMed |
description | The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or secondary resistance mechanisms. In this review, we summarize the current knowledge on the main mechanisms of resistance to targeted therapies in AML. Resistance to FLT3 inhibitors is mainly mediated by on target mutations and dysregulation of downstream pathways. Switching the FLT3 inhibitor has a potential therapeutic benefit. During treatment with IDH inhibitors resistance can develop due to aberrant cell metabolism or secondary site IDH mutations. As a unique resistance mechanism the mutated IDH isotype may switch from IDH1 to IDH2 or vice versa. Resistance to gemtuzumab-ozogamicin is determined by the CD33 isotype and the degradation of the cytotoxin. The main mechanisms of resistance to venetoclax are the dysregulation of alternative pathways especially the upregulation of the BCL-2-analogues MCL-1 and BCL-XL or the induction of an aberrant cell metabolism. The introduction of therapies targeting immune processes will lead to new forms of therapy resistance. Knowing those mechanisms will help to develop strategies that can overcome resistance to treatment. |
format | Online Article Text |
id | pubmed-9898349 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-98983492023-02-05 Resistance to targeted therapies in acute myeloid leukemia Mecklenbrauck, Rabea Heuser, Michael Clin Exp Metastasis Review The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or secondary resistance mechanisms. In this review, we summarize the current knowledge on the main mechanisms of resistance to targeted therapies in AML. Resistance to FLT3 inhibitors is mainly mediated by on target mutations and dysregulation of downstream pathways. Switching the FLT3 inhibitor has a potential therapeutic benefit. During treatment with IDH inhibitors resistance can develop due to aberrant cell metabolism or secondary site IDH mutations. As a unique resistance mechanism the mutated IDH isotype may switch from IDH1 to IDH2 or vice versa. Resistance to gemtuzumab-ozogamicin is determined by the CD33 isotype and the degradation of the cytotoxin. The main mechanisms of resistance to venetoclax are the dysregulation of alternative pathways especially the upregulation of the BCL-2-analogues MCL-1 and BCL-XL or the induction of an aberrant cell metabolism. The introduction of therapies targeting immune processes will lead to new forms of therapy resistance. Knowing those mechanisms will help to develop strategies that can overcome resistance to treatment. Springer Netherlands 2022-11-01 2023 /pmc/articles/PMC9898349/ /pubmed/36318439 http://dx.doi.org/10.1007/s10585-022-10189-0 Text en © The Author(s) 2022 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/) . |
spellingShingle | Review Mecklenbrauck, Rabea Heuser, Michael Resistance to targeted therapies in acute myeloid leukemia |
title | Resistance to targeted therapies in acute myeloid leukemia |
title_full | Resistance to targeted therapies in acute myeloid leukemia |
title_fullStr | Resistance to targeted therapies in acute myeloid leukemia |
title_full_unstemmed | Resistance to targeted therapies in acute myeloid leukemia |
title_short | Resistance to targeted therapies in acute myeloid leukemia |
title_sort | resistance to targeted therapies in acute myeloid leukemia |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898349/ https://www.ncbi.nlm.nih.gov/pubmed/36318439 http://dx.doi.org/10.1007/s10585-022-10189-0 |
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