Publicación Artículo científico (article). 2021

Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic Myeloid Leukemia

Digital.CSIC. Repositorio Institucional del CSIC
Digital.CSIC. Repositorio Institucional del CSIC
  • Contreras Mostazo, Miriam G.
  • Kurrle, Nina
  • Casado, Marta
  • Fuhrmann, Dominik
  • Alshamleh, Islam
  • Häupl, Björn
  • Martín-Sanz, Paloma
  • Brüne, Bernhard
  • Serve, Hubert
  • Schwalbe, Harald
  • Schnütgen, Frank
  • Marín, Silvia
  • Cascante, Marta
© 2020 by the authors., 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., M.G. Contreras Mostazo and I. Alshamleh were supported by the EU grant HaemMetabolome H2020-MSCA-ITN-2015-675790. H. Schwalbe, H. Serve, F. Schnütgen, S. Marin and M. Cascante acknowledge support from the European Commission (HaemMetabolome [EC-675790]). M. Cascante and S. Marin acknowledge the Spanish Ministerio de Economia y Competitividad (MINECO)-European Commission FEDER funds—“Una manera de hacer Europa” (SAF2017-89673-R), the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) Generalitat de Catalunya (2017SGR1033) and CIBERehd (CB17/04/00023) (ISCIII, Spain). M. Cascante also received support through the prize “ICREA Academia” for excellence in research, funded by ICREA foundation–Generalitat de Catalunya. F. Schnütgen was supported by the Wilhelm Sander-Foundation (2015.138.1) and the Deutsche Forschungsgemeinschaft (SCHN1166/4-1). H. Schwalbe acknowledges support for the Center for Biomolecular Magnetic Resonance (BMRZ) by state of Hesse. M. Casado and P. Martín-Sanz acknowledge support from SAF2016-75004-R (MINECO, Spain, AEI/FEDER, UE), PID2019-108977RB-I00 (MICINN, Spain,AEI/FEDER, UE), and CIBERehd (CB06/04/1069) (ISCIII, Spain). D. Fuhrmann, B. Brüne, N. Kurrle and H. Serve acknowledge Deutsche Forschungsgemeinschaft (SFB 815, TP A08, TP A10).

Digital.CSIC. Repositorio Institucional del CSIC

Digital.CSIC. Repositorio Institucional del CSIC
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Digital.CSIC. Repositorio Institucional del CSIC