The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia
The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore representing a major target for drug development in this disease. We show here that the specific mTO...
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| Veröffentlicht in: | Leukemia 2012-06, Vol.26 (6), p.1195-1202 |
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| creator | Willems, L Chapuis, N Puissant, A Maciel, T T Green, A S Jacque, N Vignon, C Park, S Guichard, S Herault, O Fricot, A Hermine, O Moura, I C Auberger, P Ifrah, N Dreyfus, F Bonnet, D Lacombe, C Mayeux, P Bouscary, D Tamburini, J |
| description | The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore representing a major target for drug development in this disease. We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials. |
| doi_str_mv | 10.1038/leu.2011.339 |
| format | Article |
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We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2011.339</identifier><identifier>PMID: 22143671</identifier><identifier>CODEN: LEUKED</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; Acute myeloid leukemia ; Adaptor Proteins, Signal Transducing - metabolism ; AKT protein ; Animals ; Anticancer properties ; Antimitotic agents ; Antineoplastic agents ; Antitumor agents ; Apoptosis ; Apoptosis - drug effects ; Autophagy ; Autophagy - drug effects ; Biological and medical sciences ; Blotting, Western ; Cancer Research ; Cancer therapies ; Caspase ; CD34 antigen ; Cell cycle ; Cell Cycle - drug effects ; Cell death ; Cell growth ; Cell proliferation ; Cell Proliferation - drug effects ; Cells, Cultured ; Cellular signal transduction ; Clinical trials ; Complications and side effects ; Critical Care Medicine ; Dosage and administration ; Drug development ; Enzyme inhibitors ; Genetic aspects ; Hematologic and hematopoietic diseases ; Hematology ; Humans ; Immunoenzyme Techniques ; Immunoprecipitation ; Initiation factor eIF-4E ; Intensive ; Internal Medicine ; Kinases ; Leukemia ; Leukemia, Myeloid, Acute - metabolism ; Leukemia, Myeloid, Acute - mortality ; Leukemia, Myeloid, Acute - prevention & control ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Mechanistic Target of Rapamycin Complex 1 ; Medical research ; Medical sciences ; Medicine ; Medicine & Public Health ; Mice ; Mice, Nude ; Morpholines - pharmacology ; Multiprotein Complexes ; Oncology ; original-article ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoproteins - metabolism ; Phosphorylation ; Phosphorylation - drug effects ; Physiological aspects ; Progenitor cells ; Protein-serine/threonine kinase ; Proteins ; Proteins - antagonists & inhibitors ; Proteins - metabolism ; Rapamycin ; Signal transduction ; Survival Rate ; TOR protein ; TOR Serine-Threonine Kinases ; Toxicity ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - metabolism ; Treatment Outcome ; Tumors ; Xenograft Model Antitumor Assays</subject><ispartof>Leukemia, 2012-06, Vol.26 (6), p.1195-1202</ispartof><rights>Macmillan Publishers Limited 2012</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jun 2012</rights><rights>Macmillan Publishers Limited 2012.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c650t-c37131a3a9bf5fb3479d7272ef1be0840728e8d5afd495bdc5af806111bac7323</citedby><cites>FETCH-LOGICAL-c650t-c37131a3a9bf5fb3479d7272ef1be0840728e8d5afd495bdc5af806111bac7323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2011.339$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2011.339$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25986187$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22143671$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Willems, L</creatorcontrib><creatorcontrib>Chapuis, N</creatorcontrib><creatorcontrib>Puissant, A</creatorcontrib><creatorcontrib>Maciel, T T</creatorcontrib><creatorcontrib>Green, A S</creatorcontrib><creatorcontrib>Jacque, N</creatorcontrib><creatorcontrib>Vignon, C</creatorcontrib><creatorcontrib>Park, S</creatorcontrib><creatorcontrib>Guichard, S</creatorcontrib><creatorcontrib>Herault, O</creatorcontrib><creatorcontrib>Fricot, A</creatorcontrib><creatorcontrib>Hermine, O</creatorcontrib><creatorcontrib>Moura, I C</creatorcontrib><creatorcontrib>Auberger, P</creatorcontrib><creatorcontrib>Ifrah, N</creatorcontrib><creatorcontrib>Dreyfus, F</creatorcontrib><creatorcontrib>Bonnet, D</creatorcontrib><creatorcontrib>Lacombe, C</creatorcontrib><creatorcontrib>Mayeux, P</creatorcontrib><creatorcontrib>Bouscary, D</creatorcontrib><creatorcontrib>Tamburini, J</creatorcontrib><title>The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore representing a major target for drug development in this disease. We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Acute myeloid leukemia</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Antimitotic agents</subject><subject>Antineoplastic agents</subject><subject>Antitumor agents</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Cancer Research</subject><subject>Cancer therapies</subject><subject>Caspase</subject><subject>CD34 antigen</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Cellular signal transduction</subject><subject>Clinical trials</subject><subject>Complications and side effects</subject><subject>Critical Care Medicine</subject><subject>Dosage and administration</subject><subject>Drug development</subject><subject>Enzyme inhibitors</subject><subject>Genetic aspects</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hematology</subject><subject>Humans</subject><subject>Immunoenzyme Techniques</subject><subject>Immunoprecipitation</subject><subject>Initiation factor eIF-4E</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Leukemia, Myeloid, Acute - mortality</subject><subject>Leukemia, Myeloid, Acute - prevention & control</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Mechanistic Target of Rapamycin Complex 1</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Morpholines - pharmacology</subject><subject>Multiprotein Complexes</subject><subject>Oncology</subject><subject>original-article</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Physiological aspects</subject><subject>Progenitor cells</subject><subject>Protein-serine/threonine kinase</subject><subject>Proteins</subject><subject>Proteins - antagonists & inhibitors</subject><subject>Proteins - metabolism</subject><subject>Rapamycin</subject><subject>Signal transduction</subject><subject>Survival Rate</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Toxicity</subject><subject>Transcription Factors - antagonists & inhibitors</subject><subject>Transcription Factors - metabolism</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp90s2L1DAUAPAgijuu3jxLQRQPdszLd4_D-AkLCzJePFjSNN3J2ja7TSrMf-8bZnR3ZZEc-kh-SV5fHiHPgS6BcvOu9_OSUYAl59UDsgChVSmlhIdkQY3RpaqYOCFPUrqkdL-oHpMTxkBwpWFBfmy2vmhn2xfD5vzrGgo7toeQFWHchibkOBWr7-8NlbLY2oQghzLPA05bl8OvkHcoMZ6zL4ad72NoC0zqpx-CfUoedbZP_tnxe0q-ffywWX8uz84_fVmvzkqnJM2l4xo4WG6rppNdw4WuWs008x00nhpBNTPetNJ2rahk0zqMDFUA0FinOeOn5M3h3KspXs8-5XoIyfm-t6OPc6qBMjxGCmGQvvyHXsZ5GjG7mikhNUhBq_8poGAUVpjKG3Vhe1-HsYt5sm5_db1iFVdKVcBRLe9ROFoskYuj7wLO39nw-taGrbd93qbYzznEMd2Fbw_QTTGlyXf11RQGO-0wyXrfHTU-RL3vjhq7A_mL40_NzeDbv_hPOyB4dQQ2Odt3kx1dSDdOVkaB0ejKg0u4NF746XZ17rn4N3_8ytw</recordid><startdate>20120601</startdate><enddate>20120601</enddate><creator>Willems, L</creator><creator>Chapuis, N</creator><creator>Puissant, A</creator><creator>Maciel, T T</creator><creator>Green, A S</creator><creator>Jacque, N</creator><creator>Vignon, C</creator><creator>Park, S</creator><creator>Guichard, S</creator><creator>Herault, O</creator><creator>Fricot, A</creator><creator>Hermine, O</creator><creator>Moura, I C</creator><creator>Auberger, P</creator><creator>Ifrah, N</creator><creator>Dreyfus, F</creator><creator>Bonnet, D</creator><creator>Lacombe, C</creator><creator>Mayeux, P</creator><creator>Bouscary, D</creator><creator>Tamburini, J</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20120601</creationdate><title>The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia</title><author>Willems, L ; 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USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Willems, L</au><au>Chapuis, N</au><au>Puissant, A</au><au>Maciel, T T</au><au>Green, A S</au><au>Jacque, N</au><au>Vignon, C</au><au>Park, S</au><au>Guichard, S</au><au>Herault, O</au><au>Fricot, A</au><au>Hermine, O</au><au>Moura, I C</au><au>Auberger, P</au><au>Ifrah, N</au><au>Dreyfus, F</au><au>Bonnet, D</au><au>Lacombe, C</au><au>Mayeux, P</au><au>Bouscary, D</au><au>Tamburini, J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2012-06-01</date><risdate>2012</risdate><volume>26</volume><issue>6</issue><spage>1195</spage><epage>1202</epage><pages>1195-1202</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><coden>LEUKED</coden><abstract>The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore representing a major target for drug development in this disease. We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22143671</pmid><doi>10.1038/leu.2011.339</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2012-06, Vol.26 (6), p.1195-1202 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1020845448 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online; EZB-FREE-00999 freely available EZB journals |
| subjects | 1-Phosphatidylinositol 3-kinase Acute myeloid leukemia Adaptor Proteins, Signal Transducing - metabolism AKT protein Animals Anticancer properties Antimitotic agents Antineoplastic agents Antitumor agents Apoptosis Apoptosis - drug effects Autophagy Autophagy - drug effects Biological and medical sciences Blotting, Western Cancer Research Cancer therapies Caspase CD34 antigen Cell cycle Cell Cycle - drug effects Cell death Cell growth Cell proliferation Cell Proliferation - drug effects Cells, Cultured Cellular signal transduction Clinical trials Complications and side effects Critical Care Medicine Dosage and administration Drug development Enzyme inhibitors Genetic aspects Hematologic and hematopoietic diseases Hematology Humans Immunoenzyme Techniques Immunoprecipitation Initiation factor eIF-4E Intensive Internal Medicine Kinases Leukemia Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - mortality Leukemia, Myeloid, Acute - prevention & control Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Mechanistic Target of Rapamycin Complex 1 Medical research Medical sciences Medicine Medicine & Public Health Mice Mice, Nude Morpholines - pharmacology Multiprotein Complexes Oncology original-article Phosphatidylinositol 3-Kinases - metabolism Phosphoproteins - metabolism Phosphorylation Phosphorylation - drug effects Physiological aspects Progenitor cells Protein-serine/threonine kinase Proteins Proteins - antagonists & inhibitors Proteins - metabolism Rapamycin Signal transduction Survival Rate TOR protein TOR Serine-Threonine Kinases Toxicity Transcription Factors - antagonists & inhibitors Transcription Factors - metabolism Treatment Outcome Tumors Xenograft Model Antitumor Assays |
| title | The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia |
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