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Trinh A, Khamari R, Fovez Q, et al. ANTIMETABOLIC COOPERATIVITY WITH THE CLINICALLY-APPROVED L-ASPARAGINASE AND TYROSINE KINASE INHIBITORS TO ERADICATE CML STEM CELLS. Mol Metab. 2021;101410doi: 10.1016/j.molmet.2021.101410.
Trinh, A., Khamari, R., Fovez, Q., Mahon, F. X., Turcq, B., Bouscary, D., Maboudou, P., Joncquel, M., Coiteux, V., Germain, N., Laine, W., Dekiouk, S., Jean-Pierre, S., Maguer-Satta, V., Ghesquiere, B., Idziorek, T., Quesnel, B., Kluza, J., & Marchetti, P. (2021). ANTIMETABOLIC COOPERATIVITY WITH THE CLINICALLY-APPROVED L-ASPARAGINASE AND TYROSINE KINASE INHIBITORS TO ERADICATE CML STEM CELLS. Molecular metabolism, 101410. https://doi.org/10.1016/j.molmet.2021.101410
Trinh, Anne, et al. "ANTIMETABOLIC COOPERATIVITY WITH THE CLINICALLY-APPROVED L-ASPARAGINASE AND TYROSINE KINASE INHIBITORS TO ERADICATE CML STEM CELLS." Molecular metabolism vol. (2021): 101410. doi: https://doi.org/10.1016/j.molmet.2021.101410
Trinh A, Khamari R, Fovez Q, Mahon FX, Turcq B, Bouscary D, Maboudou P, Joncquel M, Coiteux V, Germain N, Laine W, Dekiouk S, Jean-Pierre S, Maguer-Satta V, Ghesquiere B, Idziorek T, Quesnel B, Kluza J, Marchetti P. ANTIMETABOLIC COOPERATIVITY WITH THE CLINICALLY-APPROVED L-ASPARAGINASE AND TYROSINE KINASE INHIBITORS TO ERADICATE CML STEM CELLS. Mol Metab. 2021 Dec 01;101410. doi: 10.1016/j.molmet.2021.101410. Epub 2021 Dec 01. PMID: 34863941.
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Mol Metab. 2021 Dec 01;101410. doi: 10.1016/j.molmet.2021.101410. Epub 2021 Dec 01.

ANTIMETABOLIC COOPERATIVITY WITH THE CLINICALLY-APPROVED L-ASPARAGINASE AND TYROSINE KINASE INHIBITORS TO ERADICATE CML STEM CELLS.

Molecular metabolism

Anne Trinh, Raeeka Khamari, Quentin Fovez, François-Xavier Mahon, Béatrice Turcq, Didier Bouscary, Patrice Maboudou, Marie Joncquel, Valérie Coiteux, Nicolas Germain, William Laine, Salim Dekiouk, Sandrine Jean-Pierre, Veronique Maguer-Satta, Bart Ghesquiere, Thierry Idziorek, Bruno Quesnel, Jerome Kluza, Philippe Marchetti

Affiliations

  1. Univ. Lille, CNRS, Inserm, CHU Lille, Institut de Recherche contre le Cancer de Lille, UMR9020, UMR-S 1277, Canther, Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000, Lille, France.
  2. Institut Bergonié, Université de Bordeaux, CNRS SNC5010, Inserm, U1218 ACTION, F - 33076, Bordeaux, France.
  3. Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Service d'Hématologie clinique, Hôpital Cochin, Paris, France.
  4. Centre de Bio-Pathologie, Banque de Tissus, CHU, Lille, France.
  5. Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Centre Léon Bérard, 69008, Lyon, France.
  6. Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286.
  7. Department of Oncology and VIB, KU Leuven, Leuven, Belgium.
  8. Univ. Lille, CNRS, Inserm, CHU Lille, Institut de Recherche contre le Cancer de Lille, UMR9020, UMR-S 1277, Canther, Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000, Lille, France. Electronic address: [email protected].
  9. Univ. Lille, CNRS, Inserm, CHU Lille, Institut de Recherche contre le Cancer de Lille, UMR9020, UMR-S 1277, Canther, Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000, Lille, France; Centre de Bio-Pathologie, Banque de Tissus, CHU, Lille, France. Electronic address: [email protected].

PMID: 34863941 DOI: 10.1016/j.molmet.2021.101410

Abstract

Long-term treatment with tyrosine kinase inhibitors (TKI) represents an effective treatment for chronic myeloid leukemia (CML) and discontinuation of TKI therapy is now being proposed to patients with deep molecular responses. However, evidence demonstrating that TKI are unable to fully eradicate dormant leukemic stem cells underline that new therapeutic strategies are needed to prevent molecular relapses. We investigated metabolic pathways responsible for CML surviving Imatinib exposure and its potential therapeutic utility to improve the efficiency of TKI against CML stem cells. Using complementary cell-based techniques, we demonstrated that TKI suppressed glycolysis in a large panel of BCR-ABL1 + cell lines as well as in primary CD34+ stem-like cells from CML patients. However, compensatory glutamine-dependent mitochondrial oxidation supported ATP synthesis and CML cell survival. Glutamine metabolism was inhibited by L-asparaginases such as Kidrolase without inducing predominant CML cell death. Clinically relevant concentrations of TKI render CML progenitors and stem cells susceptible to Kidrolase. The combination of TKI with L-asparaginase reactivated the intinsic apoptotic pathway leading to efficient CML cell death. Thus, targeting glutamine metabolism with the clinically-approved drug Kidrolase, in combination with TKI which suppresses glycolysis, represents an effective and widely applicable therapeutic strategy for eradicating CML stem cells.

Copyright © 2021. Published by Elsevier GmbH.

Keywords: LSC; metabolic addiction; metabolic stress; stem-like cells; synthetic lethality

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