PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
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 prot...
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| Veröffentlicht in: | Scientific reports 2017-02, Vol.7 (1), p.43013, Article 43013 |
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| creator | Milella, Michele Falcone, Italia Conciatori, Fabiana Matteoni, Silvia Sacconi, Andrea De Luca, Teresa Bazzichetto, Chiara Corbo, Vincenzo Simbolo, Michele Sperduti, Isabella Benfante, Antonina Del Curatolo, Anais Cesta Incani, Ursula Malusa, Federico Eramo, Adriana Sette, Giovanni Scarpa, Aldo Konopleva, Marina Andreeff, Michael McCubrey, James Andrew Blandino, Giovanni Todaro, Matilde Stassi, Giorgio De Maria, Ruggero Cognetti, Francesco Del Bufalo, Donatella Ciuffreda, Ludovica |
| description | 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_str_mv | 10.1038/srep43013 |
| format | Article |
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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.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep43013</identifier><identifier>PMID: 28220839</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; 631/67/1059/602 ; 631/67/395 ; 82/80 ; 96 ; 96/1 ; 96/44 ; 96/95 ; Cancer ; Humanities and Social Sciences ; Janus kinase ; MAP kinase ; mRNA ; multidisciplinary ; PTEN protein ; Science ; Stat3 protein ; TOR protein ; Tumor cell lines</subject><ispartof>Scientific reports, 2017-02, Vol.7 (1), p.43013, Article 43013</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Feb 2017</rights><rights>Copyright © 2017, The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-e58044823e2a4a881f3fdef107b864e1857a97e61fa56ff73e71e3285b24a5943</citedby><cites>FETCH-LOGICAL-c438t-e58044823e2a4a881f3fdef107b864e1857a97e61fa56ff73e71e3285b24a5943</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318947/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318947/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28220839$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Milella, Michele</creatorcontrib><creatorcontrib>Falcone, Italia</creatorcontrib><creatorcontrib>Conciatori, Fabiana</creatorcontrib><creatorcontrib>Matteoni, Silvia</creatorcontrib><creatorcontrib>Sacconi, Andrea</creatorcontrib><creatorcontrib>De Luca, Teresa</creatorcontrib><creatorcontrib>Bazzichetto, Chiara</creatorcontrib><creatorcontrib>Corbo, Vincenzo</creatorcontrib><creatorcontrib>Simbolo, Michele</creatorcontrib><creatorcontrib>Sperduti, Isabella</creatorcontrib><creatorcontrib>Benfante, Antonina</creatorcontrib><creatorcontrib>Del Curatolo, Anais</creatorcontrib><creatorcontrib>Cesta Incani, Ursula</creatorcontrib><creatorcontrib>Malusa, Federico</creatorcontrib><creatorcontrib>Eramo, Adriana</creatorcontrib><creatorcontrib>Sette, Giovanni</creatorcontrib><creatorcontrib>Scarpa, Aldo</creatorcontrib><creatorcontrib>Konopleva, Marina</creatorcontrib><creatorcontrib>Andreeff, Michael</creatorcontrib><creatorcontrib>McCubrey, James Andrew</creatorcontrib><creatorcontrib>Blandino, Giovanni</creatorcontrib><creatorcontrib>Todaro, Matilde</creatorcontrib><creatorcontrib>Stassi, Giorgio</creatorcontrib><creatorcontrib>De Maria, Ruggero</creatorcontrib><creatorcontrib>Cognetti, Francesco</creatorcontrib><creatorcontrib>Del Bufalo, Donatella</creatorcontrib><creatorcontrib>Ciuffreda, Ludovica</creatorcontrib><title>PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>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.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>631/67/1059/602</subject><subject>631/67/395</subject><subject>82/80</subject><subject>96</subject><subject>96/1</subject><subject>96/44</subject><subject>96/95</subject><subject>Cancer</subject><subject>Humanities and Social Sciences</subject><subject>Janus kinase</subject><subject>MAP kinase</subject><subject>mRNA</subject><subject>multidisciplinary</subject><subject>PTEN protein</subject><subject>Science</subject><subject>Stat3 protein</subject><subject>TOR protein</subject><subject>Tumor cell 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Ludovica</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-02-21</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>43013</spage><pages>43013-</pages><artnum>43013</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28220839</pmid><doi>10.1038/srep43013</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 1-Phosphatidylinositol 3-kinase 631/67/1059/602 631/67/395 82/80 96 96/1 96/44 96/95 Cancer Humanities and Social Sciences Janus kinase MAP kinase mRNA multidisciplinary PTEN protein Science Stat3 protein TOR protein Tumor cell lines |
| title | PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer |
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