A key role of the WEE1-CDK1 axis in mediating TKI-therapy resistance in FLT3-ITD positive acute myeloid leukemia patients.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
28
07
2022
accepted:
02
12
2022
revised:
30
11
2022
pubmed:
13
12
2022
medline:
8
2
2023
entrez:
12
12
2022
Statut:
ppublish
Résumé
The insertion site of the internal tandem duplications (ITDs) in the FLT3 gene affects the sensitivity to tyrosine kinase inhibitors (TKIs) therapy in acute myeloid leukemia (AML). Patients with the ITD in the tyrosine kinase domain lack effective therapeutic options. Here, to identify genotype-driven strategies increasing the TKI therapy efficacy, we developed SignalingProfiler, a strategy supporting the integration of high-sensitive mass spectrometry-based (phospho)proteomics, RNA sequencing datasets with literature-derived signaling networks. The approach generated FLT3-ITD genotype-specific predictive models and revealed a conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, pharmacological inhibition of the WEE1 kinase synergizes and strengthens the pro-apoptotic effect of TKIs therapy in cell lines and patient-derived primary blasts. Finally, we propose a new molecular mechanism of TKIs resistance in AML and suggest the combination of WEE1 inhibitor and TKI as a therapeutic option to improve patients clinical outcome.
Identifiants
pubmed: 36509894
doi: 10.1038/s41375-022-01785-w
pii: 10.1038/s41375-022-01785-w
pmc: PMC9898030
doi:
Substances chimiques
Protein Kinase Inhibitors
0
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
FLT3 protein, human
EC 2.7.10.1
WEE1 protein, human
EC 2.7.10.2
Protein-Tyrosine Kinases
EC 2.7.10.1
Cell Cycle Proteins
0
CDK1 protein, human
EC 2.7.11.22
CDC2 Protein Kinase
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
288-297Informations de copyright
© 2022. The Author(s).
Références
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