A network-based approach reveals a novel mechanism of resistance to TKI-therapy in AML

ABSTRACT: 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 cells, we used high-sensitive mass spectrometry-based (phospho)proteomics and deep sequencing. Here, we developed a novel generally-applicable data analysis strategy, dubbed “Signaling Profiler”, that supports the integration of unbiased large-scale datasets with literature-derived signaling networks. The approach resulted in the generation of FLT3-ITDs specific predictive models and reveales a crucial and conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, pharmacological inhibition of the WEE1 kinase significantly synergizes and strengths 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Acute Myeloid Leukemia

SUBMITTER: Natalie Krahmer  

LAB HEAD: Natalie Krahmer

PROVIDER: PXD033953 | Pride | 2023-03-10

REPOSITORIES: Pride