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Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance

Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profil...

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Main Authors: Emdal, Kristina B. (Author) , Palacio-Escat, Nicolàs (Author) , Wigerup, Caroline (Author) , Eguchi, Akihiro (Author) , Nilsson, Helén (Author) , Bekker-Jensen, Dorte B. (Author) , Rönnstrand, Lars (Author) , Kazi, Julhash U. (Author) , Puissant, Alexandre (Author) , Itzykson, Raphaël (Author) , Sáez Rodríguez, Julio (Author) , Masson, Kristina (Author) , Blume-Jensen, Peter (Author) , Olsen, Jesper V. (Author)
Format: Article (Journal)
Language:English
Published: August 9, 2022
In: Cell reports
Year: 2022, Volume: 40, Issue: 6, Pages: 1-18, e1-e6
ISSN:2211-1247
DOI:10.1016/j.celrep.2022.111177
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2022.111177
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124722009901
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Author Notes:Kristina B. Emdal, Nicolàs Palacio-Escat, Caroline Wigerup, Akihiro Eguchi, Helén Nilsson, Dorte B. Bekker-Jensen, Lars Rönnstrand, Julhash U. Kazi, Alexandre Puissant, Raphaël Itzykson, Julio Saez-Rodriguez, Kristina Masson, Peter Blume-Jensen, and Jesper V. Olsen
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Summary:Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoproteomics in primary AML patient samples and cell lines. Functional phosphosite scoring reveals that p53 function is required for selinexor sensitivity consistent with enhanced efficacy of selinexor in combination with the MDM2 inhibitor nutlin-3a. Moreover, combining selinexor with the AKT inhibitor MK-2206 overcomes dysregulated AKT-FOXO3 signaling in resistant cells, resulting in synergistic anti-proliferative effects. Using high-throughput spatial proteomics to profile subcellular compartments, we measure global proteome and phospho-proteome dynamics, providing direct evidence of nuclear translocation of FOXO3 upon combination treatment. Our data demonstrate the potential of phosphoproteomics and functional phosphorylation site scoring to successfully pinpoint key targetable signaling hubs for rational drug combinations.
Item Description:Gesehen am 27.01.2023
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2022.111177

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