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Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia
SIMPLE SUMMARY: Tyrosine kinase inhibitors (TKIs), such as imatinib, have become the standard initial treatment of choice for chronic myeloid leukemia (CML) patients. However, one obstacle to face is that a significant proportion of patients presents poor response to TKIs, or acquires resistance res...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699488/ https://www.ncbi.nlm.nih.gov/pubmed/33228196 http://dx.doi.org/10.3390/cancers12113443 |
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author | Mostazo, Miriam G. Contreras Kurrle, Nina Casado, Marta Fuhrmann, Dominik Alshamleh, Islam Häupl, Björn Martín-Sanz, Paloma Brüne, Bernhard Serve, Hubert Schwalbe, Harald Schnütgen, Frank Marin, Silvia Cascante, Marta |
author_facet | Mostazo, Miriam G. Contreras Kurrle, Nina Casado, Marta Fuhrmann, Dominik Alshamleh, Islam Häupl, Björn Martín-Sanz, Paloma Brüne, Bernhard Serve, Hubert Schwalbe, Harald Schnütgen, Frank Marin, Silvia Cascante, Marta |
author_sort | Mostazo, Miriam G. Contreras |
collection | PubMed |
description | SIMPLE SUMMARY: Tyrosine kinase inhibitors (TKIs), such as imatinib, have become the standard initial treatment of choice for chronic myeloid leukemia (CML) patients. However, one obstacle to face is that a significant proportion of patients presents poor response to TKIs, or acquires resistance resulting in disease relapses. Mutations in BCR-ABL1 protein are a well described mechanism of resistance but other not well established mechanisms outside BCR-ABL1 mutations are emerging as important in the acquisition of resistance. Abnormal metabolism of CML cells that acquire resistance to imatinib has been pointed out as a putative downstream key event, but deep studies aimed to unveil metabolic adaptations associated with acquired resistance are still lacking. Here, we perform an exhaustive study on metabolic reprogramming associated with acquired imatinib resistance and we identify metabolic vulnerabilities of CML imatinib resistant cells that could pave the way for new therapies targeting TKI failure. ABSTRACT: Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML. |
format | Online Article Text |
id | pubmed-7699488 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76994882020-11-29 Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia Mostazo, Miriam G. Contreras Kurrle, Nina Casado, Marta Fuhrmann, Dominik Alshamleh, Islam Häupl, Björn Martín-Sanz, Paloma Brüne, Bernhard Serve, Hubert Schwalbe, Harald Schnütgen, Frank Marin, Silvia Cascante, Marta Cancers (Basel) Article SIMPLE SUMMARY: Tyrosine kinase inhibitors (TKIs), such as imatinib, have become the standard initial treatment of choice for chronic myeloid leukemia (CML) patients. However, one obstacle to face is that a significant proportion of patients presents poor response to TKIs, or acquires resistance resulting in disease relapses. Mutations in BCR-ABL1 protein are a well described mechanism of resistance but other not well established mechanisms outside BCR-ABL1 mutations are emerging as important in the acquisition of resistance. Abnormal metabolism of CML cells that acquire resistance to imatinib has been pointed out as a putative downstream key event, but deep studies aimed to unveil metabolic adaptations associated with acquired resistance are still lacking. Here, we perform an exhaustive study on metabolic reprogramming associated with acquired imatinib resistance and we identify metabolic vulnerabilities of CML imatinib resistant cells that could pave the way for new therapies targeting TKI failure. ABSTRACT: Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML. MDPI 2020-11-19 /pmc/articles/PMC7699488/ /pubmed/33228196 http://dx.doi.org/10.3390/cancers12113443 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mostazo, Miriam G. Contreras Kurrle, Nina Casado, Marta Fuhrmann, Dominik Alshamleh, Islam Häupl, Björn Martín-Sanz, Paloma Brüne, Bernhard Serve, Hubert Schwalbe, Harald Schnütgen, Frank Marin, Silvia Cascante, Marta Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia |
title | Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia |
title_full | Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia |
title_fullStr | Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia |
title_full_unstemmed | Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia |
title_short | Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia |
title_sort | metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in chronic myeloid leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699488/ https://www.ncbi.nlm.nih.gov/pubmed/33228196 http://dx.doi.org/10.3390/cancers12113443 |
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