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Phosphoproteomics o...
Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance
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- Emdal, Kristina B. (author)
- University of Copenhagen
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- Palacio-Escat, Nicolàs (author)
- RWTH Aachen University,University Hospital Heidelberg,Heidelberg University
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- Wigerup, Caroline (author)
- Acrivon Therapeutics Inc.
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- Eguchi, Akihiro (author)
- University of Copenhagen
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- Nilsson, Helén (author)
- Acrivon Therapeutics Inc.
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- Bekker-Jensen, Dorte B. (author)
- University of Copenhagen
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- Rönnstrand, Lars (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Molekylär cancerforskning,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Stem Cell Center,Division of stem cell research,Molecular Cancer Research,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Kazi, Julhash U. (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Puissant, Alexandre (author)
- Saint-Louis Hospital, Paris
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- Itzykson, Raphaël (author)
- Saint-Louis Hospital, Paris
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- Saez-Rodriguez, Julio (author)
- RWTH Aachen University,University Hospital Heidelberg
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Masson, Kristina (author)
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Blume-Jensen, Peter (author)
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- Olsen, Jesper V. (author)
- University of Copenhagen
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(creator_code:org_t)
- Elsevier BV, 2022
- 2022
- English.
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 40:6
- Related links:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- acute myeloid leukemia
- combination therapy
- CP: Cancer
- CP: Molecular biology
- drug resistance
- functional scoring
- mass spectrometry
- MK-2206
- nutlin-3a
- phosphoproteomics
- selinexor
- subcellular proteomics
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Emdal, Kristina ...
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Palacio-Escat, N ...
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Wigerup, Carolin ...
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Eguchi, Akihiro
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Nilsson, Helén
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Bekker-Jensen, D ...
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show more...
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Rönnstrand, Lars
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Kazi, Julhash U.
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Puissant, Alexan ...
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Itzykson, Raphaë ...
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Saez-Rodriguez, ...
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Masson, Kristina
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Blume-Jensen, Pe ...
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Olsen, Jesper V.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Cell Reports
- By the university
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Lund University