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1.
Elife ; 122024 Apr 02.
Article in English | MEDLINE | ID: mdl-38564252

ABSTRACT

Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.


Subject(s)
Leukemia, Myeloid, Acute , Signal Transduction , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , MAP Kinase Signaling System , Cell Line , Drug Resistance , fms-Like Tyrosine Kinase 3/genetics
3.
Leukemia ; 37(2): 288-297, 2023 02.
Article in English | MEDLINE | ID: mdl-36509894

ABSTRACT

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.


Subject(s)
Leukemia, Myeloid, Acute , Protein Kinase Inhibitors , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Drug Resistance, Neoplasm/genetics , Cell Line , Signal Transduction , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolism , Mutation , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , CDC2 Protein Kinase/genetics , CDC2 Protein Kinase/metabolism , CDC2 Protein Kinase/pharmacology
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