TY  - JOUR
A1  - Contreras Mostazo, Miriam Guadalupe
A1  - Kurrle, Nina Susanne
A1  - Casado, Marta
A1  - Fuhrmann, Dominik Christian
A1  - Alshamleh, Islam
A1  - Häupl, Björn
A1  - Martín-Sanz, Paloma
A1  - Brüne, Bernhard
A1  - Serve, Hubert
A1  - Schwalbe, Harald
A1  - Schnütgen, Frank
A1  - Marin, Silvia
A1  - Cascante, Marta
T1  - Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in chronic myeloid leukemia
T2  - Cancers
N2  - 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.
KW  - chronic myeloid leukemia
KW  - metabolic reprogramming
KW  - proteomics
KW  - tyrosine kinase inhibitors.
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/57409
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-574091
SN  - 2072-6694
VL  - 12
IS  - Article 3443
PB  - MDPI
CY  - Basel
ER  -