eEF2K Activity Determines Synergy to Cotreatment of Cancer Cells With PI3K and MEK Inhibitors |
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| Authors: | Maruan Hijazi Pedro Casado Nosheen Akhtar Saul Alvarez-Teijeiro Vinothini Rajeeve Pedro R. Cutillas |
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| Affiliation: | 1. Signalling & Proteomics Group, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;2. The Alan Turing Institute, British Library, London, United Kingdom |
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| Abstract: | 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. |
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| Keywords: | phosphoproteomics kinase activity eEF2K cancer AML biomarkers synergy combination therapy 4EBP1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0055" }," $$" :[{" #name" :" text" ," _" :" eukaryotic translation initiation factor 4E-binding protein 1 ACN" },{" #name" :" keyword" ," $" :{" id" :" kwrd0065" }," $$" :[{" #name" :" text" ," _" :" acetonitrile AML" },{" #name" :" keyword" ," $" :{" id" :" kwrd0075" }," $$" :[{" #name" :" text" ," _" :" acute myeloid leukemia CDI" },{" #name" :" keyword" ," $" :{" id" :" kwrd0085" }," $$" :[{" #name" :" text" ," _" :" coefficient of drug interaction DMSO" },{" #name" :" keyword" ," $" :{" id" :" kwrd0095" }," $$" :[{" #name" :" text" ," _" :" dimethyl sulfoxide eEF2" },{" #name" :" keyword" ," $" :{" id" :" kwrd0105" }," $$" :[{" #name" :" text" ," _" :" eukaryotic elongation factor 2 eEF2K" },{" #name" :" keyword" ," $" :{" id" :" kwrd0115" }," $$" :[{" #name" :" text" ," _" :" eukaryotic elongation factor 2 kinase ERK" },{" #name" :" keyword" ," $" :{" id" :" kwrd0125" }," $$" :[{" #name" :" text" ," _" :" extracellular signal-related kinase FBS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0135" }," $$" :[{" #name" :" text" ," _" :" fetal bovine serum FDA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0145" }," $$" :[{" #name" :" text" ," _" :" Food and Drug Administration HEL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0155" }," $$" :[{" #name" :" text" ," _" :" human erythroleukemia IRS1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0165" }," $$" :[{" #name" :" text" ," _" :" insulin receptor substrate 1 JNK1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0175" }," $$" :[{" #name" :" text" ," _" :" c-Jun N-terminal kinase 1 LDS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0185" }," $$" :[{" #name" :" text" ," _" :" lithium dodecyl sulfate MCF7" },{" #name" :" keyword" ," $" :{" id" :" kwrd0195" }," $$" :[{" #name" :" text" ," _" :" Michigan Cancer Foundation-7 MEK" },{" #name" :" keyword" ," $" :{" id" :" kwrd0205" }," $$" :[{" #name" :" text" ," _" :" MAPK/ERK kinase MAPK" },{" #name" :" keyword" ," $" :{" id" :" kwrd0215" }," $$" :[{" #name" :" text" ," _" :" mitogen-activated protein kinase MOPS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0225" }," $$" :[{" #name" :" text" ," _" :" 3-(N-morpholino) propanesulfonic acid MS/MS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0235" }," $$" :[{" #name" :" text" ," _" :" tandem mass spectrometry mTOR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0245" }," $$" :[{" #name" :" text" ," _" :" mammalian target of rapamycin NaF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0255" }," $$" :[{" #name" :" text" ," _" :" sodium fluoride PRAS40" },{" #name" :" keyword" ," $" :{" id" :" kwrd0265" }," $$" :[{" #name" :" text" ," _" :" proline-rich AKT1 substrate 1 RIPA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0275" }," $$" :[{" #name" :" text" ," _" :" radioimmunoprecipitation assay THP-1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0285" }," $$" :[{" #name" :" text" ," _" :" Tohoku Hospital Pediatrics-1 TiO2" },{" #name" :" keyword" ," $" :{" id" :" kwrd0295" }," $$" :[{" #name" :" text" ," _" :" titanium dioxide XIC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0305" }," $$" :[{" #name" :" text" ," _" :" extracted ion chromatogram |
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