Contreras Mostazo 2020 Cancers (Basel)

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Publications in the MiPMap
Mostazo MGC, Kurrle N, Casado M, Fuhrmann D, Alshamleh I, Häupl B, Martín-Sanz P, Brüne B, Serve H, Schwalbe H, Schnütgen F, Marin S, Cascante M (2020) Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Cancers (Basel) 12:E3443.

» PMID: 33228196 Open Access

Contreras Mostazo Miriam G, Kurrle Nina, Casado Marta, Fuhrmann Dominik, Alshamleh Islam, Haeupl Bjoern, Martin-Sanz Paloma, Bruene Bernhard, Serve Hubert, Schwalbe Harald, Schnuetgen Frank, Marin Silvia, Cascante Marta (2020) Cancers (Basel)

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.

Keywords: Chronic myeloid leukemia, Metabolic reprogramming, Proteomics, Tyrosine kinase inhibitors Bioblast editor: Plangger M O2k-Network Lab: ES Valencia Casado Pinna M

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cancer 

Organism: Human  Tissue;cell: Blood cells  Preparation: Permeabilized cells, Intact cells 

Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: F, N, S, Gp, CIV, ROX  HRR: Oxygraph-2k