Klin Padiatr 2022; 234(03): 178
DOI: 10.1055/s-0042-1748697
Abstracts

Targeting metabolism effectively complements tyrosine kinase inhibitor treatment of chronic myeloid leukemia

L Häselbarth
1   Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University (FAU) Erlangen–Nuremberg, Germany
,
D Saul
2   Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Germany
,
M Krumbholz
1   Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University (FAU) Erlangen–Nuremberg, Germany
,
D Mougiakaos
3   Department of Hematology and Oncology, University Hospital Magdeburg, Germany
,
M Metzler
1   Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University (FAU) Erlangen–Nuremberg, Germany
,
A Karow
1   Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University (FAU) Erlangen–Nuremberg, Germany
› Author Affiliations
 

Tyrosine kinase inhibitors (TKI), targeting the BCR/ABL1 fusion protein, like imatinib, dasatinib, nilotinib and the first-in-class myristoyl pocket targeting TKI asciminib have revolutionized the treatment options of chronic myeloid leukemia (CML). However, resistance to therapy, relapse after treatment termination and side effects are problems of long-term TKI-treatment. Therefore, it is important to optimize TKI therapy and to investigate additional therapeutic approaches. Here, we tested how different TKI affect the metabolism of CML cells and whether the synergistic lethality can be increased by inhibition of different checkpoints such as the respiratory chain and the unfolded protein response (UPR). We found that glucose metabolism was strongly impaired by TKI and that an additional inhibition of complex I (rotenone) or V (oligomycin) of the respiratory chain caused an increased cell death. Similar results were obtained when generating ER-stress by thapsigargin in TKI-treated CML cells, which might be due to a TKI-induced UPR-inhibition. All in all, we hypothesize that TKI treatment is more effective by additional inhibition of glucose metabolism and by ER-stress induction.



Publication History

Article published online:
17 May 2022

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