Leukemia, 2023-02, Vol.37 (2), p.288-297
2023
Details
- Autor(en) / Beteiligte
- Titel
- A key role of the WEE1-CDK1 axis in mediating TKI-therapy resistance in FLT3-ITD positive acute myeloid leukemia patients
- Ist Teil von
- Leukemia, 2023-02, Vol.37 (2), p.288-297
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2023
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0887-6924eISSN: 1476-5551DOI: 10.1038/s41375-022-01785-wTitel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9898030
- Format
- –
- Schlagworte
- Acute myeloid leukemia, Apoptosis, Biology, CDC2 Protein Kinase - genetics, CDC2 Protein Kinase - metabolism, CDC2 Protein Kinase - pharmacology, Cell Cycle Proteins - genetics, Cell Cycle Proteins - metabolism, Cell Line, Cells, Chemotherapy, Diabetes, Drug Resistance, Neoplasm - genetics, Flow cytometry, FLT3 gene, fms-Like Tyrosine Kinase 3 - genetics, fms-Like Tyrosine Kinase 3 - metabolism, Gene sequencing, Genes, Genotypes, Humans, Kinases, Leukemia, Leukemia, Myeloid, Acute - drug therapy, Leukemia, Myeloid, Acute - genetics, Mass spectrometry, Mass spectroscopy, Mutation, Patients, Prediction models, Protein Kinase Inhibitors - pharmacology, Protein Kinase Inhibitors - therapeutic use, Protein-tyrosine kinase, Protein-Tyrosine Kinases - genetics, Protein-Tyrosine Kinases - metabolism, Proteins, Proteomics, Signal Transduction, Therapy, Tyrosine