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Title: Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia
Author: Contreras Mostazo, Míriam G.
Kurrle, Nina
Casado, Marta
Fuhrmann, Dominik
Alshamleh, Islam
Häupl, Björn
Martín Sanz, Paloma
Brüne, Bernhard, 1957-
Serve, Hubert
Schwalbe, Harald
Schnütgen, Frank
Marín Martínez, Silvia
Cascante i Serratosa, Marta
Keywords: Leucèmia mieloide
Leucèmia aguda
Myeloid leukemia
Acute leukemia
Issue Date: 19-Nov-2020
Publisher: MDPI
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.
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It is part of: Cancers, 2020, vol. 12(11), num. 3443
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ISSN: 2072-6694
Appears in Collections:Articles publicats en revistes (Institut de Biomedicina (IBUB))
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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