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

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

  • Cell Rep. 2022 Aug 9;40(6):111177. doi: 10.1016/j.celrep.2022.111177.
Kristina B Emdal 1 Nicolàs Palacio-Escat 2 Caroline Wigerup 3 Akihiro Eguchi 1 Helén Nilsson 3 Dorte B Bekker-Jensen 1 Lars Rönnstrand 4 Julhash U Kazi 4 Alexandre Puissant 5 Raphaël Itzykson 5 Julio Saez-Rodriguez 6 Kristina Masson 7 Peter Blume-Jensen 8 Jesper V Olsen 9
Affiliations

Affiliations

  • 1 Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 2 Heidelberg University, Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, BioQuant-Zentrum, Heidelberg, Germany; Heidelberg University, Faculty of Biosciences, Heidelberg, Germany; RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine, Aachen, Germany.
  • 3 Acrivon Therapeutics Inc., Watertown, MA, USA.
  • 4 Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • 5 INSERM UMR 944, IRSL, St Louis Hospital, Paris, France.
  • 6 Heidelberg University, Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, BioQuant-Zentrum, Heidelberg, Germany; RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine, Aachen, Germany. Electronic address: [email protected].
  • 7 Acrivon Therapeutics Inc., Watertown, MA, USA. Electronic address: [email protected].
  • 8 Acrivon Therapeutics Inc., Watertown, MA, USA. Electronic address: [email protected].
  • 9 Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: [email protected].
Abstract

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.

Keywords

CP: Cancer; CP: Molecular biology; MK-2206; acute myeloid leukemia; combination therapy; drug resistance; functional scoring; mass spectrometry; nutlin-3a; phosphoproteomics; selinexor; subcellular proteomics.

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