PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.
Identifieur interne : 000872 ( Main/Corpus ); précédent : 000871; suivant : 000873PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.
Auteurs : Michele Milella ; Italia Falcone ; Fabiana Conciatori ; Silvia Matteoni ; Andrea Sacconi ; Teresa De Luca ; Chiara Bazzichetto ; Vincenzo Corbo ; Michele Simbolo ; Isabella Sperduti ; Antonina Benfante ; Anais Del Curatolo ; Ursula Cesta Incani ; Federico Malusa ; Adriana Eramo ; Giovanni Sette ; Aldo Scarpa ; Marina Konopleva ; Michael Andreeff ; James Andrew Mccubrey ; Giovanni Blandino ; Matilde Todaro ; Giorgio Stassi ; Ruggero De Maria ; Francesco Cognetti ; Donatella Del Bufalo ; Ludovica CiuffredaSource :
- Scientific reports [ 2045-2322 ] ; 2017.
English descriptors
- KwdEn :
- Animals (MeSH), Cell Line, Tumor (MeSH), Drug Synergism (MeSH), Everolimus (pharmacology), Female (MeSH), Humans (MeSH), Janus Kinase 1 (genetics), Janus Kinase 1 (metabolism), MAP Kinase Kinase Kinases (antagonists & inhibitors), MAP Kinase Kinase Kinases (metabolism), Mice (MeSH), Mice, Nude (MeSH), Neoplastic Stem Cells (cytology), Neoplastic Stem Cells (drug effects), Neoplastic Stem Cells (metabolism), PTEN Phosphohydrolase (antagonists & inhibitors), PTEN Phosphohydrolase (genetics), PTEN Phosphohydrolase (metabolism), Phosphatidylinositol 3-Kinases (metabolism), Phosphoinositide-3 Kinase Inhibitors (MeSH), Protein Kinase Inhibitors (pharmacology), Proto-Oncogene Proteins c-akt (antagonists & inhibitors), Proto-Oncogene Proteins c-akt (metabolism), Pyridones (pharmacology), Pyrimidinones (pharmacology), RNA Interference (MeSH), RNA, Small Interfering (metabolism), STAT3 Transcription Factor (genetics), STAT3 Transcription Factor (metabolism), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , antagonists & inhibitors : MAP Kinase Kinase Kinases, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , genetics : Janus Kinase 1, PTEN Phosphohydrolase, STAT3 Transcription Factor.
- chemical , metabolism : Janus Kinase 1, MAP Kinase Kinase Kinases, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-akt, RNA, Small Interfering, STAT3 Transcription Factor, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Everolimus, Protein Kinase Inhibitors, Pyridones, Pyrimidinones.
- cytology : Neoplastic Stem Cells.
- drug effects : Neoplastic Stem Cells.
- metabolism : Neoplastic Stem Cells, Phosphatidylinositol 3-Kinases.
- Animals, Cell Line, Tumor, Drug Synergism, Female, Humans, Mice, Mice, Nude, Phosphoinositide-3 Kinase Inhibitors, RNA Interference.
Abstract
Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies.
DOI: 10.1038/srep43013
PubMed: 28220839
PubMed Central: PMC5318947
Links to Exploration step
pubmed:28220839Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.</title><author><name sortKey="Milella, Michele" sort="Milella, Michele" uniqKey="Milella M" first="Michele" last="Milella">Michele Milella</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Falcone, Italia" sort="Falcone, Italia" uniqKey="Falcone I" first="Italia" last="Falcone">Italia Falcone</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Conciatori, Fabiana" sort="Conciatori, Fabiana" uniqKey="Conciatori F" first="Fabiana" last="Conciatori">Fabiana Conciatori</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Matteoni, Silvia" sort="Matteoni, Silvia" uniqKey="Matteoni S" first="Silvia" last="Matteoni">Silvia Matteoni</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Sacconi, Andrea" sort="Sacconi, Andrea" uniqKey="Sacconi A" first="Andrea" last="Sacconi">Andrea Sacconi</name><affiliation><nlm:affiliation>Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="De Luca, Teresa" sort="De Luca, Teresa" uniqKey="De Luca T" first="Teresa" last="De Luca">Teresa De Luca</name><affiliation><nlm:affiliation>Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Bazzichetto, Chiara" sort="Bazzichetto, Chiara" uniqKey="Bazzichetto C" first="Chiara" last="Bazzichetto">Chiara Bazzichetto</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Corbo, Vincenzo" sort="Corbo, Vincenzo" uniqKey="Corbo V" first="Vincenzo" last="Corbo">Vincenzo Corbo</name><affiliation><nlm:affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Simbolo, Michele" sort="Simbolo, Michele" uniqKey="Simbolo M" first="Michele" last="Simbolo">Michele Simbolo</name><affiliation><nlm:affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Sperduti, Isabella" sort="Sperduti, Isabella" uniqKey="Sperduti I" first="Isabella" last="Sperduti">Isabella Sperduti</name><affiliation><nlm:affiliation>Biostatistics, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Benfante, Antonina" sort="Benfante, Antonina" uniqKey="Benfante A" first="Antonina" last="Benfante">Antonina Benfante</name><affiliation><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Del Curatolo, Anais" sort="Del Curatolo, Anais" uniqKey="Del Curatolo A" first="Anais" last="Del Curatolo">Anais Del Curatolo</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Cesta Incani, Ursula" sort="Cesta Incani, Ursula" uniqKey="Cesta Incani U" first="Ursula" last="Cesta Incani">Ursula Cesta Incani</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Malusa, Federico" sort="Malusa, Federico" uniqKey="Malusa F" first="Federico" last="Malusa">Federico Malusa</name><affiliation><nlm:affiliation>Data Analysis Unit, Siena Biotech S.p.A. Siena, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Eramo, Adriana" sort="Eramo, Adriana" uniqKey="Eramo A" first="Adriana" last="Eramo">Adriana Eramo</name><affiliation><nlm:affiliation>Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Sette, Giovanni" sort="Sette, Giovanni" uniqKey="Sette G" first="Giovanni" last="Sette">Giovanni Sette</name><affiliation><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Scarpa, Aldo" sort="Scarpa, Aldo" uniqKey="Scarpa A" first="Aldo" last="Scarpa">Aldo Scarpa</name><affiliation><nlm:affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Konopleva, Marina" sort="Konopleva, Marina" uniqKey="Konopleva M" first="Marina" last="Konopleva">Marina Konopleva</name><affiliation><nlm:affiliation>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston (TX), USA.</nlm:affiliation></affiliation></author><author><name sortKey="Andreeff, Michael" sort="Andreeff, Michael" uniqKey="Andreeff M" first="Michael" last="Andreeff">Michael Andreeff</name><affiliation><nlm:affiliation>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston (TX), USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mccubrey, James Andrew" sort="Mccubrey, James Andrew" uniqKey="Mccubrey J" first="James Andrew" last="Mccubrey">James Andrew Mccubrey</name><affiliation><nlm:affiliation>Department of Microbiology &Immunology, Brody School of Medicine, East Carolina University, Greenville (NC), USA.</nlm:affiliation></affiliation></author><author><name sortKey="Blandino, Giovanni" sort="Blandino, Giovanni" uniqKey="Blandino G" first="Giovanni" last="Blandino">Giovanni Blandino</name><affiliation><nlm:affiliation>Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Todaro, Matilde" sort="Todaro, Matilde" uniqKey="Todaro M" first="Matilde" last="Todaro">Matilde Todaro</name><affiliation><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Stassi, Giorgio" sort="Stassi, Giorgio" uniqKey="Stassi G" first="Giorgio" last="Stassi">Giorgio Stassi</name><affiliation><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="De Maria, Ruggero" sort="De Maria, Ruggero" uniqKey="De Maria R" first="Ruggero" last="De Maria">Ruggero De Maria</name><affiliation><nlm:affiliation>Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Cognetti, Francesco" sort="Cognetti, Francesco" uniqKey="Cognetti F" first="Francesco" last="Cognetti">Francesco Cognetti</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Del Bufalo, Donatella" sort="Del Bufalo, Donatella" uniqKey="Del Bufalo D" first="Donatella" last="Del Bufalo">Donatella Del Bufalo</name><affiliation><nlm:affiliation>Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Ciuffreda, Ludovica" sort="Ciuffreda, Ludovica" uniqKey="Ciuffreda L" first="Ludovica" last="Ciuffreda">Ludovica Ciuffreda</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28220839</idno><idno type="pmid">28220839</idno><idno type="doi">10.1038/srep43013</idno><idno type="pmc">PMC5318947</idno><idno type="wicri:Area/Main/Corpus">000872</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000872</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.</title><author><name sortKey="Milella, Michele" sort="Milella, Michele" uniqKey="Milella M" first="Michele" last="Milella">Michele Milella</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Falcone, Italia" sort="Falcone, Italia" uniqKey="Falcone I" first="Italia" last="Falcone">Italia Falcone</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Conciatori, Fabiana" sort="Conciatori, Fabiana" uniqKey="Conciatori F" first="Fabiana" last="Conciatori">Fabiana Conciatori</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Matteoni, Silvia" sort="Matteoni, Silvia" uniqKey="Matteoni S" first="Silvia" last="Matteoni">Silvia Matteoni</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Sacconi, Andrea" sort="Sacconi, Andrea" uniqKey="Sacconi A" first="Andrea" last="Sacconi">Andrea Sacconi</name><affiliation><nlm:affiliation>Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="De Luca, Teresa" sort="De Luca, Teresa" uniqKey="De Luca T" first="Teresa" last="De Luca">Teresa De Luca</name><affiliation><nlm:affiliation>Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Bazzichetto, Chiara" sort="Bazzichetto, Chiara" uniqKey="Bazzichetto C" first="Chiara" last="Bazzichetto">Chiara Bazzichetto</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Corbo, Vincenzo" sort="Corbo, Vincenzo" uniqKey="Corbo V" first="Vincenzo" last="Corbo">Vincenzo Corbo</name><affiliation><nlm:affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Simbolo, Michele" sort="Simbolo, Michele" uniqKey="Simbolo M" first="Michele" last="Simbolo">Michele Simbolo</name><affiliation><nlm:affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Sperduti, Isabella" sort="Sperduti, Isabella" uniqKey="Sperduti I" first="Isabella" last="Sperduti">Isabella Sperduti</name><affiliation><nlm:affiliation>Biostatistics, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Benfante, Antonina" sort="Benfante, Antonina" uniqKey="Benfante A" first="Antonina" last="Benfante">Antonina Benfante</name><affiliation><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Del Curatolo, Anais" sort="Del Curatolo, Anais" uniqKey="Del Curatolo A" first="Anais" last="Del Curatolo">Anais Del Curatolo</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Cesta Incani, Ursula" sort="Cesta Incani, Ursula" uniqKey="Cesta Incani U" first="Ursula" last="Cesta Incani">Ursula Cesta Incani</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Malusa, Federico" sort="Malusa, Federico" uniqKey="Malusa F" first="Federico" last="Malusa">Federico Malusa</name><affiliation><nlm:affiliation>Data Analysis Unit, Siena Biotech S.p.A. Siena, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Eramo, Adriana" sort="Eramo, Adriana" uniqKey="Eramo A" first="Adriana" last="Eramo">Adriana Eramo</name><affiliation><nlm:affiliation>Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Sette, Giovanni" sort="Sette, Giovanni" uniqKey="Sette G" first="Giovanni" last="Sette">Giovanni Sette</name><affiliation><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Scarpa, Aldo" sort="Scarpa, Aldo" uniqKey="Scarpa A" first="Aldo" last="Scarpa">Aldo Scarpa</name><affiliation><nlm:affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Konopleva, Marina" sort="Konopleva, Marina" uniqKey="Konopleva M" first="Marina" last="Konopleva">Marina Konopleva</name><affiliation><nlm:affiliation>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston (TX), USA.</nlm:affiliation></affiliation></author><author><name sortKey="Andreeff, Michael" sort="Andreeff, Michael" uniqKey="Andreeff M" first="Michael" last="Andreeff">Michael Andreeff</name><affiliation><nlm:affiliation>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston (TX), USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mccubrey, James Andrew" sort="Mccubrey, James Andrew" uniqKey="Mccubrey J" first="James Andrew" last="Mccubrey">James Andrew Mccubrey</name><affiliation><nlm:affiliation>Department of Microbiology &Immunology, Brody School of Medicine, East Carolina University, Greenville (NC), USA.</nlm:affiliation></affiliation></author><author><name sortKey="Blandino, Giovanni" sort="Blandino, Giovanni" uniqKey="Blandino G" first="Giovanni" last="Blandino">Giovanni Blandino</name><affiliation><nlm:affiliation>Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Todaro, Matilde" sort="Todaro, Matilde" uniqKey="Todaro M" first="Matilde" last="Todaro">Matilde Todaro</name><affiliation><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Stassi, Giorgio" sort="Stassi, Giorgio" uniqKey="Stassi G" first="Giorgio" last="Stassi">Giorgio Stassi</name><affiliation><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="De Maria, Ruggero" sort="De Maria, Ruggero" uniqKey="De Maria R" first="Ruggero" last="De Maria">Ruggero De Maria</name><affiliation><nlm:affiliation>Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Cognetti, Francesco" sort="Cognetti, Francesco" uniqKey="Cognetti F" first="Francesco" last="Cognetti">Francesco Cognetti</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Del Bufalo, Donatella" sort="Del Bufalo, Donatella" uniqKey="Del Bufalo D" first="Donatella" last="Del Bufalo">Donatella Del Bufalo</name><affiliation><nlm:affiliation>Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Ciuffreda, Ludovica" sort="Ciuffreda, Ludovica" uniqKey="Ciuffreda L" first="Ludovica" last="Ciuffreda">Ludovica Ciuffreda</name><affiliation><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Scientific reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Cell Line, Tumor (MeSH)</term><term>Drug Synergism (MeSH)</term><term>Everolimus (pharmacology)</term><term>Female (MeSH)</term><term>Humans (MeSH)</term><term>Janus Kinase 1 (genetics)</term><term>Janus Kinase 1 (metabolism)</term><term>MAP Kinase Kinase Kinases (antagonists & inhibitors)</term><term>MAP Kinase Kinase Kinases (metabolism)</term><term>Mice (MeSH)</term><term>Mice, Nude (MeSH)</term><term>Neoplastic Stem Cells (cytology)</term><term>Neoplastic Stem Cells (drug effects)</term><term>Neoplastic Stem Cells (metabolism)</term><term>PTEN Phosphohydrolase (antagonists & inhibitors)</term><term>PTEN Phosphohydrolase (genetics)</term><term>PTEN Phosphohydrolase (metabolism)</term><term>Phosphatidylinositol 3-Kinases (metabolism)</term><term>Phosphoinositide-3 Kinase Inhibitors (MeSH)</term><term>Protein Kinase Inhibitors (pharmacology)</term><term>Proto-Oncogene Proteins c-akt (antagonists & inhibitors)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Pyridones (pharmacology)</term><term>Pyrimidinones (pharmacology)</term><term>RNA Interference (MeSH)</term><term>RNA, Small Interfering (metabolism)</term><term>STAT3 Transcription Factor (genetics)</term><term>STAT3 Transcription Factor (metabolism)</term><term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term><term>TOR Serine-Threonine Kinases (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>MAP Kinase Kinase Kinases</term><term>PTEN Phosphohydrolase</term><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Janus Kinase 1</term><term>PTEN Phosphohydrolase</term><term>STAT3 Transcription Factor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Janus Kinase 1</term><term>MAP Kinase Kinase Kinases</term><term>PTEN Phosphohydrolase</term><term>Proto-Oncogene Proteins c-akt</term><term>RNA, Small Interfering</term><term>STAT3 Transcription Factor</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Everolimus</term><term>Protein Kinase Inhibitors</term><term>Pyridones</term><term>Pyrimidinones</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Neoplastic Stem Cells</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Neoplastic Stem Cells</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neoplastic Stem Cells</term><term>Phosphatidylinositol 3-Kinases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Drug Synergism</term><term>Female</term><term>Humans</term><term>Mice</term><term>Mice, Nude</term><term>Phosphoinositide-3 Kinase Inhibitors</term><term>RNA Interference</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28220839</PMID><DateCompleted><Year>2018</Year><Month>10</Month><Day>30</Day></DateCompleted><DateRevised><Year>2019</Year><Month>12</Month><Day>10</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2045-2322</ISSN><JournalIssue CitedMedium="Internet"><Volume>7</Volume><PubDate><Year>2017</Year><Month>02</Month><Day>21</Day></PubDate></JournalIssue><Title>Scientific reports</Title><ISOAbbreviation>Sci Rep</ISOAbbreviation></Journal><ArticleTitle>PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.</ArticleTitle><Pagination><MedlinePgn>43013</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/srep43013</ELocationID><Abstract><AbstractText>Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Milella</LastName><ForeName>Michele</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Falcone</LastName><ForeName>Italia</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Conciatori</LastName><ForeName>Fabiana</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Matteoni</LastName><ForeName>Silvia</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sacconi</LastName><ForeName>Andrea</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Luca</LastName><ForeName>Teresa</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bazzichetto</LastName><ForeName>Chiara</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Corbo</LastName><ForeName>Vincenzo</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Simbolo</LastName><ForeName>Michele</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sperduti</LastName><ForeName>Isabella</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Biostatistics, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Benfante</LastName><ForeName>Antonina</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Del Curatolo</LastName><ForeName>Anais</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cesta Incani</LastName><ForeName>Ursula</ForeName><Initials>U</Initials><AffiliationInfo><Affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Malusa</LastName><ForeName>Federico</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Data Analysis Unit, Siena Biotech S.p.A. Siena, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Eramo</LastName><ForeName>Adriana</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sette</LastName><ForeName>Giovanni</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Scarpa</LastName><ForeName>Aldo</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Konopleva</LastName><ForeName>Marina</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston (TX), USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Andreeff</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston (TX), USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McCubrey</LastName><ForeName>James Andrew</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>Department of Microbiology &Immunology, Brody School of Medicine, East Carolina University, Greenville (NC), USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blandino</LastName><ForeName>Giovanni</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Todaro</LastName><ForeName>Matilde</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stassi</LastName><ForeName>Giorgio</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Maria</LastName><ForeName>Ruggero</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cognetti</LastName><ForeName>Francesco</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Del Bufalo</LastName><ForeName>Donatella</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ciuffreda</LastName><ForeName>Ludovica</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>02</Month><Day>21</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Sci Rep</MedlineTA><NlmUniqueID>101563288</NlmUniqueID><ISSNLinking>2045-2322</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000081082">Phosphoinositide-3 Kinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D047428">Protein Kinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011728">Pyridones</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011744">Pyrimidinones</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D034741">RNA, Small Interfering</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D050796">STAT3 Transcription Factor</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C494086">STAT3 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>33E86K87QN</RegistryNumber><NameOfSubstance UI="C560077">trametinib</NameOfSubstance></Chemical><Chemical><RegistryNumber>9HW64Q8G6G</RegistryNumber><NameOfSubstance UI="D000068338">Everolimus</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546842">MTOR protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.2</RegistryNumber><NameOfSubstance UI="C507904">JAK1 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.2</RegistryNumber><NameOfSubstance UI="D053613">Janus Kinase 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D051057">Proto-Oncogene Proteins c-akt</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.25</RegistryNumber><NameOfSubstance UI="D020930">MAP Kinase Kinase Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.1.3.67</RegistryNumber><NameOfSubstance UI="D051059">PTEN Phosphohydrolase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.1.3.67</RegistryNumber><NameOfSubstance UI="C494929">PTEN protein, human</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004357" MajorTopicYN="N">Drug Synergism</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000068338" MajorTopicYN="N">Everolimus</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053613" MajorTopicYN="N">Janus Kinase 1</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020930" MajorTopicYN="N">MAP Kinase Kinase Kinases</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008819" MajorTopicYN="N">Mice, Nude</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014411" MajorTopicYN="N">Neoplastic Stem Cells</DescriptorName><QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051059" MajorTopicYN="N">PTEN Phosphohydrolase</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019869" MajorTopicYN="N">Phosphatidylinositol 3-Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000081082" MajorTopicYN="N">Phosphoinositide-3 Kinase Inhibitors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D047428" MajorTopicYN="N">Protein Kinase Inhibitors</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051057" MajorTopicYN="N">Proto-Oncogene Proteins c-akt</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011728" MajorTopicYN="N">Pyridones</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011744" MajorTopicYN="N">Pyrimidinones</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D034622" MajorTopicYN="N">RNA Interference</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D034741" MajorTopicYN="N">RNA, Small Interfering</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D050796" MajorTopicYN="N">STAT3 Transcription Factor</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>08</Month><Day>26</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2017</Year><Month>01</Month><Day>18</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>2</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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