A key role of the WEE1-CDK1 axis in mediating TKI-therapy resistance in FLT3-ITD positive acute myeloid leukemia patients

Internal tandem duplications (ITDs) in the FLT3 gene are frequently identified and confer a poor prognosis in patient affected by acute myeloid leukemia (AML). The insertion site of the ITDs in FLT3 significantly impacts the sensitivity to tyrosine kinase inhibitors (TKIs) therapy, affecting patient...

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Published inbioRxiv
Main Authors Massacci, Giorgia, Venafra, Veronica, Latini, Sara, Bica, Valeria, Giusj Monia Pugliese, Klingelhuber, Felix, Krahmer, Natalie, Fischer, Thomas, Mougiakakos, Dimitrios, Boettcher, Martin, Perfetto, Livia, Sacco, Francesca
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 16.05.2022
Subjects
Acute myeloid leukemia
Apoptosis
FLT3 gene
Kinases
Leukemia
Mass spectroscopy
Molecular modelling
Patients
Prediction models
Protein-tyrosine kinase
Proteomics
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Summary:Internal tandem duplications (ITDs) in the FLT3 gene are frequently identified and confer a poor prognosis in patient affected by acute myeloid leukemia (AML). The insertion site of the ITDs in FLT3 significantly impacts the sensitivity to tyrosine kinase inhibitors (TKIs) therapy, affecting patient's clinical outcome. To decipher the molecular mechanisms driving the different sensitivity to TKIs therapy of FLT3-ITD mutation, we used high-sensitive mass spectrometry-based (phospho)proteomics and deep sequencing. Here, we present a novel generally-applicable strategy that supports the integration of unbiased large-scale datasets with literature-derived signaling networks. The approach produced FLT3-ITDs specific predictive models and revealed a crucial and conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, we found that pharmacological inhibition of the WEE1 kinase synergizes and strengthens the pro-apoptotic effect of TKIs therapy in cell lines and patient-derived primary blasts. In conclusion, this work proposes a new molecular mechanism of TKIs resistance in AML and suggests a combination therapy as option to improve therapeutic efficacy. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2022.05.16.492070