RapamycinFungusV1, Main, Exploration, bibRecord, 000778

PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.

Identifieur interne : 000778 ( Main/Exploration ); précédent : 000777; suivant : 000779

PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.

Auteurs : Michele Milella [Italie] ; Italia Falcone [Italie] ; Fabiana Conciatori [Italie] ; Silvia Matteoni [Italie] ; Andrea Sacconi [Italie] ; Teresa De Luca [Italie] ; Chiara Bazzichetto [Italie] ; Vincenzo Corbo [Italie] ; Michele Simbolo [Italie] ; Isabella Sperduti [Italie] ; Antonina Benfante [Italie] ; Anais Del Curatolo [Italie] ; Ursula Cesta Incani [Italie] ; Federico Malusa [Italie] ; Adriana Eramo [Italie] ; Giovanni Sette [Italie] ; Aldo Scarpa [Italie] ; Marina Konopleva [États-Unis] ; Michael Andreeff [États-Unis] ; James Andrew Mccubrey [États-Unis] ; Giovanni Blandino [Italie] ; Matilde Todaro [Italie] ; Giorgio Stassi [Italie] ; Ruggero De Maria [Italie] ; Francesco Cognetti [Italie] ; Donatella Del Bufalo [Italie] ; Ludovica Ciuffreda [Italie]

Source :

Scientific reports [ 2045-2322 ] ; 2017.

RBID : pubmed:28220839

Descripteurs français

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

Affiliations:

Links toward previous steps (curation, corpus...)

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Le document en format XML

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<author><name sortKey="Blandino, Giovanni" sort="Blandino, Giovanni" uniqKey="Blandino G" first="Giovanni" last="Blandino">Giovanni Blandino</name>
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<author><name sortKey="Bazzichetto, Chiara" sort="Bazzichetto, Chiara" uniqKey="Bazzichetto C" first="Chiara" last="Bazzichetto">Chiara Bazzichetto</name>
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<author><name sortKey="Corbo, Vincenzo" sort="Corbo, Vincenzo" uniqKey="Corbo V" first="Vincenzo" last="Corbo">Vincenzo Corbo</name>
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</affiliation>
</author>
<author><name sortKey="Simbolo, Michele" sort="Simbolo, Michele" uniqKey="Simbolo M" first="Michele" last="Simbolo">Michele Simbolo</name>
<affiliation wicri:level="1"><nlm:affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona</wicri:regionArea>
<wicri:noRegion>Verona</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Sperduti, Isabella" sort="Sperduti, Isabella" uniqKey="Sperduti I" first="Isabella" last="Sperduti">Isabella Sperduti</name>
<affiliation wicri:level="3"><nlm:affiliation>Biostatistics, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Biostatistics, Regina Elena National Cancer Institute, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Benfante, Antonina" sort="Benfante, Antonina" uniqKey="Benfante A" first="Antonina" last="Benfante">Antonina Benfante</name>
<affiliation wicri:level="1"><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>DiBiMIS, University of Palermo, Palermo</wicri:regionArea>
<wicri:noRegion>Palermo</wicri:noRegion>
</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 wicri:level="3"><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Medical Oncology 1, Regina Elena National Cancer Institute, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</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 wicri:level="3"><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Medical Oncology 1, Regina Elena National Cancer Institute, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Malusa, Federico" sort="Malusa, Federico" uniqKey="Malusa F" first="Federico" last="Malusa">Federico Malusa</name>
<affiliation wicri:level="1"><nlm:affiliation>Data Analysis Unit, Siena Biotech S.p.A. Siena, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Data Analysis Unit, Siena Biotech S.p.A. Siena</wicri:regionArea>
<wicri:noRegion>Siena Biotech S.p.A. Siena</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Eramo, Adriana" sort="Eramo, Adriana" uniqKey="Eramo A" first="Adriana" last="Eramo">Adriana Eramo</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sette, Giovanni" sort="Sette, Giovanni" uniqKey="Sette G" first="Giovanni" last="Sette">Giovanni Sette</name>
<affiliation wicri:level="1"><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>DiBiMIS, University of Palermo, Palermo</wicri:regionArea>
<wicri:noRegion>Palermo</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Scarpa, Aldo" sort="Scarpa, Aldo" uniqKey="Scarpa A" first="Aldo" last="Scarpa">Aldo Scarpa</name>
<affiliation wicri:level="1"><nlm:affiliation>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>ARC-Net Research Centre and Department of Pathology, University of Verona, Verona</wicri:regionArea>
<wicri:noRegion>Verona</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Konopleva, Marina" sort="Konopleva, Marina" uniqKey="Konopleva M" first="Marina" last="Konopleva">Marina Konopleva</name>
<affiliation wicri:level="1"><nlm:affiliation>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of  Texas MD Anderson Cancer Center, Houston (TX), USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of  Texas MD Anderson Cancer Center, Houston (TX)</wicri:regionArea>
<wicri:noRegion>Houston (TX)</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Andreeff, Michael" sort="Andreeff, Michael" uniqKey="Andreeff M" first="Michael" last="Andreeff">Michael Andreeff</name>
<affiliation wicri:level="1"><nlm:affiliation>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of  Texas MD Anderson Cancer Center, Houston (TX), USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Section of Molecular Hematology and Therapy, Department of Leukemia, The University of  Texas MD Anderson Cancer Center, Houston (TX)</wicri:regionArea>
<wicri:noRegion>Houston (TX)</wicri:noRegion>
</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 wicri:level="1"><nlm:affiliation>Department of Microbiology &Immunology, Brody School of Medicine, East Carolina University, Greenville (NC), USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology &Immunology, Brody School of Medicine, East Carolina University, Greenville (NC)</wicri:regionArea>
<wicri:noRegion>Greenville (NC)</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Blandino, Giovanni" sort="Blandino, Giovanni" uniqKey="Blandino G" first="Giovanni" last="Blandino">Giovanni Blandino</name>
<affiliation wicri:level="3"><nlm:affiliation>Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Todaro, Matilde" sort="Todaro, Matilde" uniqKey="Todaro M" first="Matilde" last="Todaro">Matilde Todaro</name>
<affiliation wicri:level="1"><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>DiBiMIS, University of Palermo, Palermo</wicri:regionArea>
<wicri:noRegion>Palermo</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Stassi, Giorgio" sort="Stassi, Giorgio" uniqKey="Stassi G" first="Giorgio" last="Stassi">Giorgio Stassi</name>
<affiliation wicri:level="1"><nlm:affiliation>DiBiMIS, University of Palermo, Palermo, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>DiBiMIS, University of Palermo, Palermo</wicri:regionArea>
<wicri:noRegion>Palermo</wicri:noRegion>
</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 wicri:level="3"><nlm:affiliation>Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Scientific Direction, Regina Elena National Cancer Institute, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cognetti, Francesco" sort="Cognetti, Francesco" uniqKey="Cognetti F" first="Francesco" last="Cognetti">Francesco Cognetti</name>
<affiliation wicri:level="3"><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Medical Oncology 1, Regina Elena National Cancer Institute, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</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 wicri:level="3"><nlm:affiliation>Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ciuffreda, Ludovica" sort="Ciuffreda, Ludovica" uniqKey="Ciuffreda L" first="Ludovica" last="Ciuffreda">Ludovica Ciuffreda</name>
<affiliation wicri:level="3"><nlm:affiliation>Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Medical Oncology 1, Regina Elena National Cancer Institute, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</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>
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<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="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Cellules souches tumorales (cytologie)</term>
<term>Cellules souches tumorales (effets des médicaments et des substances chimiques)</term>
<term>Cellules souches tumorales (métabolisme)</term>
<term>Facteur de transcription STAT-3 (génétique)</term>
<term>Facteur de transcription STAT-3 (métabolisme)</term>
<term>Femelle (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Inhibiteurs de protéines kinases (pharmacologie)</term>
<term>Interférence par ARN (MeSH)</term>
<term>Janus kinase 1 (génétique)</term>
<term>Janus kinase 1 (métabolisme)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>MAP Kinase Kinase Kinases (antagonistes et inhibiteurs)</term>
<term>MAP Kinase Kinase Kinases (métabolisme)</term>
<term>Petit ARN interférent (métabolisme)</term>
<term>Phosphatidylinositol 3-kinases (métabolisme)</term>
<term>Phosphohydrolase PTEN (antagonistes et inhibiteurs)</term>
<term>Phosphohydrolase PTEN (génétique)</term>
<term>Phosphohydrolase PTEN (métabolisme)</term>
<term>Protéines proto-oncogènes c-akt (antagonistes et inhibiteurs)</term>
<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
<term>Pyridones (pharmacologie)</term>
<term>Pyrimidinones (pharmacologie)</term>
<term>Souris (MeSH)</term>
<term>Souris nude (MeSH)</term>
<term>Synergie des médicaments (MeSH)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Sérine-thréonine kinases TOR (métabolisme)</term>
<term>Évérolimus (pharmacologie)</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="antagonistes et inhibiteurs" xml:lang="fr"><term>MAP Kinase Kinase Kinases</term>
<term>Phosphohydrolase PTEN</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Cellules souches tumorales</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="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Cellules souches tumorales</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteur de transcription STAT-3</term>
<term>Janus kinase 1</term>
<term>Phosphohydrolase PTEN</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neoplastic Stem Cells</term>
<term>Phosphatidylinositol 3-Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cellules souches tumorales</term>
<term>Facteur de transcription STAT-3</term>
<term>Janus kinase 1</term>
<term>MAP Kinase Kinase Kinases</term>
<term>Petit ARN interférent</term>
<term>Phosphatidylinositol 3-kinases</term>
<term>Phosphohydrolase PTEN</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de protéines kinases</term>
<term>Pyridones</term>
<term>Pyrimidinones</term>
<term>Évérolimus</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>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Femelle</term>
<term>Humains</term>
<term>Interférence par ARN</term>
<term>Lignée cellulaire tumorale</term>
<term>Souris</term>
<term>Souris nude</term>
<term>Synergie des médicaments</term>
</keywords>
</textClass>
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<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>
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<name sortKey="Malusa, Federico" sort="Malusa, Federico" uniqKey="Malusa F" first="Federico" last="Malusa">Federico Malusa</name>
<name sortKey="Matteoni, Silvia" sort="Matteoni, Silvia" uniqKey="Matteoni S" first="Silvia" last="Matteoni">Silvia Matteoni</name>
<name sortKey="Sacconi, Andrea" sort="Sacconi, Andrea" uniqKey="Sacconi A" first="Andrea" last="Sacconi">Andrea Sacconi</name>
<name sortKey="Scarpa, Aldo" sort="Scarpa, Aldo" uniqKey="Scarpa A" first="Aldo" last="Scarpa">Aldo Scarpa</name>
<name sortKey="Sette, Giovanni" sort="Sette, Giovanni" uniqKey="Sette G" first="Giovanni" last="Sette">Giovanni Sette</name>
<name sortKey="Simbolo, Michele" sort="Simbolo, Michele" uniqKey="Simbolo M" first="Michele" last="Simbolo">Michele Simbolo</name>
<name sortKey="Sperduti, Isabella" sort="Sperduti, Isabella" uniqKey="Sperduti I" first="Isabella" last="Sperduti">Isabella Sperduti</name>
<name sortKey="Stassi, Giorgio" sort="Stassi, Giorgio" uniqKey="Stassi G" first="Giorgio" last="Stassi">Giorgio Stassi</name>
<name sortKey="Todaro, Matilde" sort="Todaro, Matilde" uniqKey="Todaro M" first="Matilde" last="Todaro">Matilde Todaro</name>
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<name sortKey="Mccubrey, James Andrew" sort="Mccubrey, James Andrew" uniqKey="Mccubrey J" first="James Andrew" last="Mccubrey">James Andrew Mccubrey</name>
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   |clé=     pubmed:28220839
   |texte=   PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.
}}

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	Serveur d'exploration sur la rapamycine et les champignons
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Serveur d'exploration sur la rapamycine et les champignons

PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.

PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.

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