Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in chronic myeloid leukemia

  • 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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Author:Miriam Guadalupe Contreras MostazoORCiDGND, Nina Susanne KurrleORCiDGND, Marta CasadoORCiD, Dominik Christian FuhrmannORCiDGND, Islam Alshamleh, Björn Häupl, Paloma Martín-Sanz, Bernhard BrüneORCiD, Hubert ServeORCiDGND, Harald SchwalbeORCiDGND, Frank SchnütgenORCiDGND, Silvia MarinORCiD, Marta CascanteORCiD
Pubmed Id:
Parent Title (English):Cancers
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/11/19
Date of first Publication:2020/11/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/12/23
Tag:chronic myeloid leukemia; metabolic reprogramming; proteomics; tyrosine kinase inhibitors.
Issue:Article 3443
Page Number:26
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0