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

• DOI: 10.1038/s41375-022-01785-w
• Publication Date: 2022-12-12T11:03:05Z
• Authors: Giorgia Massacci; Veronica Venafra; Sara Latini; Valeria Bica; Giusj Monia Pugliese; Simone Graziosi; Felix Klingelhuber; Natalie Krahmer; Thomas Fischer; Dimitrios Mougiak...; Martin Boettcher; Livia Perfetto; Francesca Sacco
• Keywords: Wee1; Targeted Therapy

Abstract The insertion site of the internal tandem duplications (ITDs) in FLT3 gene affects sensitivity to tyrosine kinase inhibitors (TKIs) therapy acute myeloid leukemia (AML). Patients with ITD domain lack effective therapeutic options. Here, identify genotype-driven strategies increasing TKI efficacy, we developed SignalingProfiler , a strategy supporting integration high-sensitive mass spectrometry-based (phospho)proteomics, RNA sequencing datasets literature-derived signaling networks. approach generated FLT3-ITD genotype-specific predictive models and revealed conserved role WEE1-CDK1 axis TKIs resistance. Remarkably, pharmacological inhibition WEE1 synergizes strengthens pro-apoptotic effect cell lines patient-derived primary blasts. Finally, propose new molecular mechanism resistance AML suggest combination inhibitor as option improve patients clinical outcome.