eEF2K Activity Determines Synergy to Cotreatment of Cancer Cells With PI3K and MEK Inhibitors.

Cell Line, Tumor Chromatography, Liquid Mitogen-Activated Protein Kinase Kinases Neoplasms / drug therapy Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / pharmacology Tandem Mass Spectrometry
AML biomarkers cancer combination therapy eEF2K kinase activity phosphoproteomics synergy

Journal

Molecular & cellular proteomics : MCP
ISSN: 1535-9484
Titre abrégé: Mol Cell Proteomics
Pays: United States
ID NLM: 101125647

Informations de publication

Date de publication:
06 2022
Historique:
received: 30 09 2021
revised: 17 03 2022
accepted: 25 04 2022
pubmed: 6 5 2022
medline: 29 6 2022
entrez: 5 5 2022
Statut: ppublish

Résumé

PI3K-mammalian target of rapamycin and MAPK/ERK kinase (MEK)/mitogen-activated protein kinase (MAPK) are the most frequently dysregulated signaling pathways in cancer. A problem that limits the success of therapies that target individual PI3K-MAPK members is that these pathways converge to regulate downstream functions and often compensate each other, leading to drug resistance and transient responses to therapy. In order to overcome resistance, therapies based on cotreatments with PI3K/AKT and MEK/MAPK inhibitors are now being investigated in clinical trials, but the mechanisms of sensitivity to cotreatment are not fully understood. Using LC-MS/MS-based phosphoproteomics, we found that eukaryotic elongation factor 2 kinase (eEF2K), a key convergence point downstream of MAPK and PI3K pathways, mediates synergism to cotreatment with trametinib plus pictilisib (which target MEK1/2 and PI3Kα/δ, respectively). Inhibition of eEF2K by siRNA or with a small molecule inhibitor reversed the antiproliferative effects of the cotreatment with PI3K plus MEK inhibitors in a cell model-specific manner. Systematic analysis in 12 acute myeloid leukemia cell lines revealed that eEF2K activity was increased in cells for which PI3K plus MEKi cotreatment is synergistic, while PKC potentially mediated resistance to such cotreatment. Together, our study uncovers eEF2K activity as a key mediator of responses to PI3Ki plus MEKi and as a potential biomarker to predict synergy to cotreatment in cancer cells.

Identifiants

DOI: 10.1016/j.mcpro.2022.100240 PMID: 35513296 PMC: PMC9184568
pubmed: 35513296
pii: S1535-9476(22)00048-2
doi: 10.1016/j.mcpro.2022.100240
pmc: PMC9184568
pii:
doi:

Substances chimiques

Phosphoinositide-3 Kinase Inhibitors 0
Protein Kinase Inhibitors 0
Mitogen-Activated Protein Kinase Kinases EC 2.7.12.2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

100240

Subventions

Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M006174/1
Pays : United Kingdom

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interests P. R. C. is a co-founder of Kinomica Ltd. The other authors declare no competing interests.

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Auteurs

Maruan Hijazi (M)

Signalling & Proteomics Group, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Electronic address: m.hijazivega@qmul.ac.uk.

Pedro Casado (P)

Signalling & Proteomics Group, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Nosheen Akhtar (N)

Signalling & Proteomics Group, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Saul Alvarez-Teijeiro (S)

Signalling & Proteomics Group, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Vinothini Rajeeve (V)

Signalling & Proteomics Group, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Pedro R Cutillas (PR)

Signalling & Proteomics Group, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; The Alan Turing Institute, British Library, London, United Kingdom. Electronic address: p.cutillas@qmul.ac.uk.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › eEF2K Activity Determines Synergy to...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Chromatographie › Chromatographie en phase liquide › eEF2K Activity Determines Synergy to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › Mitogen-Activated Protein Kinase Kinases › eEF2K Activity Determines Synergy to...
questionsmedicales.fr › Tumeurs › eEF2K Activity Determines Synergy to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › eEF2K Activity Determines Synergy to...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs des phosphoinositide-3 kinases › eEF2K Activity Determines Synergy to...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › eEF2K Activity Determines Synergy to...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Spectrométrie de masse › Spectrométrie de masse en tandem › eEF2K Activity Determines Synergy to...