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Massacci, G.* ; Venafra, V.* ; Latini, S.* ; Bica, V.* ; Pugliese, G.M.* ; Graziosi, S.* ; Klingelhuber, F. ; Krahmer, N. ; Fischer, T.* ; Mougiakakos, D.* ; Boettcher, M.* ; Perfetto, L.* ; Sacco, F.*

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

Leukemia 37, 288-297 (2022)

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	Open Access Gold (Paid Option)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Wee1 Kinase; Inhibition; Mutations; Signor; Cells; Aml

ISSN (print) / ISBN 0887-6924

e-ISSN 1476-5551

Journal Leukemia

Quellenangaben Volume: 37, Issue: 2, Pages: 288-297

Publisher Nature Publishing Group

Publishing Place Campus, 4 Crinan St, London, N1 9xw, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)

Grants AIRC
Italian Association for Cancer Research (AIRC)