RapamycinFungusV1, Main, Exploration, bibRecord, 000272

NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.

Identifieur interne : 000272 ( Main/Exploration ); précédent : 000271; suivant : 000273

NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.

Auteurs : Anahita Dastur [États-Unis] ; Ahyun Choi [États-Unis] ; Carlotta Costa [États-Unis] ; Xunqin Yin [États-Unis] ; August Williams [États-Unis] ; Joseph Mcclanaghan [États-Unis] ; Max Greenberg [États-Unis] ; Justine Roderick [États-Unis] ; Neha U. Patel [États-Unis] ; Jessica Boisvert [États-Unis] ; Ultan Mcdermott [Royaume-Uni] ; Mathew J. Garnett [Royaume-Uni] ; Jorge Almenara [États-Unis] ; Steven Grant [États-Unis] ; Kathryn Rizzo [États-Unis] ; Jeffrey A. Engelman [États-Unis] ; Michelle Kelliher [États-Unis] ; Anthony C. Faber [États-Unis] ; Cyril H. Benes [États-Unis]

Source :

Clinical cancer research : an official journal of the American Association for Cancer Research [ 1078-0432 ] ; 2019.

RBID : pubmed:30224339

Descripteurs français

KwdFr :
- Amyloid precursor protein secretases (antagonistes et inhibiteurs), Amyloid precursor protein secretases (génétique), Animaux (MeSH), Apoptose (effets des médicaments et des substances chimiques), Complexe-1 cible mécanistique de la rapamycine (génétique), Dérivés de l'aniline (pharmacologie), Humains (MeSH), Hétérogreffes (MeSH), Leucémie-lymphome lymphoblastique à précurseurs T (anatomopathologie), Leucémie-lymphome lymphoblastique à précurseurs T (génétique), Leucémie-lymphome lymphoblastique à précurseurs T (traitement médicamenteux), Lignée cellulaire tumorale (MeSH), Prolifération cellulaire (effets des médicaments et des substances chimiques), Protéine Mcl-1 (génétique), Récepteur Notch1 (génétique), Résistance aux médicaments antinéoplasiques (effets des médicaments et des substances chimiques), Résistance aux médicaments antinéoplasiques (génétique), Souris (MeSH), Sulfonamides (pharmacologie), Transduction du signal (effets des médicaments et des substances chimiques).
MESH :
- anatomopathologie : Leucémie-lymphome lymphoblastique à précurseurs T.
- antagonistes et inhibiteurs : Amyloid precursor protein secretases.
- effets des médicaments et des substances chimiques : Apoptose, Prolifération cellulaire, Résistance aux médicaments antinéoplasiques, Transduction du signal.
- génétique : Amyloid precursor protein secretases, Complexe-1 cible mécanistique de la rapamycine, Leucémie-lymphome lymphoblastique à précurseurs T, Protéine Mcl-1, Récepteur Notch1, Résistance aux médicaments antinéoplasiques.
- pharmacologie : Dérivés de l'aniline, Sulfonamides.
- traitement médicamenteux : Leucémie-lymphome lymphoblastique à précurseurs T.
- Animaux, Humains, Hétérogreffes, Lignée cellulaire tumorale, Souris.

English descriptors

KwdEn :
- Amyloid Precursor Protein Secretases (antagonists & inhibitors), Amyloid Precursor Protein Secretases (genetics), Aniline Compounds (pharmacology), Animals (MeSH), Apoptosis (drug effects), Cell Line, Tumor (MeSH), Cell Proliferation (drug effects), Drug Resistance, Neoplasm (drug effects), Drug Resistance, Neoplasm (genetics), Heterografts (MeSH), Humans (MeSH), Mechanistic Target of Rapamycin Complex 1 (genetics), Mice (MeSH), Myeloid Cell Leukemia Sequence 1 Protein (genetics), Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy), Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics), Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (pathology), Receptor, Notch1 (genetics), Signal Transduction (drug effects), Sulfonamides (pharmacology).
MESH :
- chemical , antagonists & inhibitors : Amyloid Precursor Protein Secretases.
- chemical , genetics : Amyloid Precursor Protein Secretases, Mechanistic Target of Rapamycin Complex 1, Myeloid Cell Leukemia Sequence 1 Protein, Receptor, Notch1.
- chemical , pharmacology : Aniline Compounds, Sulfonamides.
- drug effects : Apoptosis, Cell Proliferation, Drug Resistance, Neoplasm, Signal Transduction.
- drug therapy : Precursor T-Cell Lymphoblastic Leukemia-Lymphoma.
- genetics : Drug Resistance, Neoplasm, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma.
- pathology : Precursor T-Cell Lymphoblastic Leukemia-Lymphoma.
- Animals, Cell Line, Tumor, Heterografts, Humans, Mice.

Abstract

PURPOSE

Effective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL.

EXPERIMENTAL DESIGN

We performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both

RESULTS

We found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax

CONCLUSIONS

Our results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.

DOI: 10.1158/1078-0432.CCR-18-0867
PubMed: 30224339
PubMed Central: PMC6320296

Affiliations:

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

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Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en">NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.</title>
<author><name sortKey="Dastur, Anahita" sort="Dastur, Anahita" uniqKey="Dastur A" first="Anahita" last="Dastur">Anahita Dastur</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
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<author><name sortKey="Choi, Ahyun" sort="Choi, Ahyun" uniqKey="Choi A" first="Ahyun" last="Choi">Ahyun Choi</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester</wicri:cityArea>
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<author><name sortKey="Costa, Carlotta" sort="Costa, Carlotta" uniqKey="Costa C" first="Carlotta" last="Costa">Carlotta Costa</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
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<author><name sortKey="Yin, Xunqin" sort="Yin, Xunqin" uniqKey="Yin X" first="Xunqin" last="Yin">Xunqin Yin</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Williams, August" sort="Williams, August" uniqKey="Williams A" first="August" last="Williams">August Williams</name>
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</placeName>
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<author><name sortKey="Mcclanaghan, Joseph" sort="Mcclanaghan, Joseph" uniqKey="Mcclanaghan J" first="Joseph" last="Mcclanaghan">Joseph Mcclanaghan</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
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<author><name sortKey="Greenberg, Max" sort="Greenberg, Max" uniqKey="Greenberg M" first="Max" last="Greenberg">Max Greenberg</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston</wicri:cityArea>
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<author><name sortKey="Roderick, Justine" sort="Roderick, Justine" uniqKey="Roderick J" first="Justine" last="Roderick">Justine Roderick</name>
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<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Patel, Neha U" sort="Patel, Neha U" uniqKey="Patel N" first="Neha U" last="Patel">Neha U. Patel</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Virginie</region>
</placeName>
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</author>
<author><name sortKey="Boisvert, Jessica" sort="Boisvert, Jessica" uniqKey="Boisvert J" first="Jessica" last="Boisvert">Jessica Boisvert</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mcdermott, Ultan" sort="Mcdermott, Ultan" uniqKey="Mcdermott U" first="Ultan" last="Mcdermott">Ultan Mcdermott</name>
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<author><name sortKey="Garnett, Mathew J" sort="Garnett, Mathew J" uniqKey="Garnett M" first="Mathew J" last="Garnett">Mathew J. Garnett</name>
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<wicri:noRegion>Cambridgeshire</wicri:noRegion>
</affiliation>
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<author><name sortKey="Almenara, Jorge" sort="Almenara, Jorge" uniqKey="Almenara J" first="Jorge" last="Almenara">Jorge Almenara</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Virginie</region>
</placeName>
<wicri:cityArea>Department of Anatomic Pathology, Virginia Commonwealth University, Richmond</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Grant, Steven" sort="Grant, Steven" uniqKey="Grant S" first="Steven" last="Grant">Steven Grant</name>
<affiliation wicri:level="2"><nlm:affiliation>Departments of Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, The Institute for Molecular Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Virginie</region>
</placeName>
<wicri:cityArea>Departments of Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, The Institute for Molecular Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Rizzo, Kathryn" sort="Rizzo, Kathryn" uniqKey="Rizzo K" first="Kathryn" last="Rizzo">Kathryn Rizzo</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Anatomic Pathology, Virginia Commonwealth University, Richmond, Virginia.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Virginie</region>
</placeName>
<wicri:cityArea>Department of Anatomic Pathology, Virginia Commonwealth University, Richmond</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Engelman, Jeffrey A" sort="Engelman, Jeffrey A" uniqKey="Engelman J" first="Jeffrey A" last="Engelman">Jeffrey A. Engelman</name>
<affiliation wicri:level="2"><nlm:affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Harvard Medical School, Boston, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Department of Medicine, Harvard Medical School, Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Kelliher, Michelle" sort="Kelliher, Michelle" uniqKey="Kelliher M" first="Michelle" last="Kelliher">Michelle Kelliher</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Faber, Anthony C" sort="Faber, Anthony C" uniqKey="Faber A" first="Anthony C" last="Faber">Anthony C. Faber</name>
<affiliation wicri:level="2"><nlm:affiliation>VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Virginie</region>
</placeName>
<wicri:cityArea>VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Benes, Cyril H" sort="Benes, Cyril H" uniqKey="Benes C" first="Cyril H" last="Benes">Cyril H. Benes</name>
<affiliation wicri:level="2"><nlm:affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts. cbenes@mgh.harvard.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Harvard Medical School, Boston, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Department of Medicine, Harvard Medical School, Boston</wicri:cityArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Clinical cancer research : an official journal of the American Association for Cancer Research</title>
<idno type="ISSN">1078-0432</idno>
<imprint><date when="2019" type="published">2019</date>
</imprint>
</series>
</biblStruct>
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</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amyloid Precursor Protein Secretases (antagonists & inhibitors)</term>
<term>Amyloid Precursor Protein Secretases (genetics)</term>
<term>Aniline Compounds (pharmacology)</term>
<term>Animals (MeSH)</term>
<term>Apoptosis (drug effects)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Cell Proliferation (drug effects)</term>
<term>Drug Resistance, Neoplasm (drug effects)</term>
<term>Drug Resistance, Neoplasm (genetics)</term>
<term>Heterografts (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (genetics)</term>
<term>Mice (MeSH)</term>
<term>Myeloid Cell Leukemia Sequence 1 Protein (genetics)</term>
<term>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)</term>
<term>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics)</term>
<term>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (pathology)</term>
<term>Receptor, Notch1 (genetics)</term>
<term>Signal Transduction (drug effects)</term>
<term>Sulfonamides (pharmacology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Amyloid precursor protein secretases (antagonistes et inhibiteurs)</term>
<term>Amyloid precursor protein secretases (génétique)</term>
<term>Animaux (MeSH)</term>
<term>Apoptose (effets des médicaments et des substances chimiques)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (génétique)</term>
<term>Dérivés de l'aniline (pharmacologie)</term>
<term>Humains (MeSH)</term>
<term>Hétérogreffes (MeSH)</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs T (anatomopathologie)</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs T (génétique)</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs T (traitement médicamenteux)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Prolifération cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Protéine Mcl-1 (génétique)</term>
<term>Récepteur Notch1 (génétique)</term>
<term>Résistance aux médicaments antinéoplasiques (effets des médicaments et des substances chimiques)</term>
<term>Résistance aux médicaments antinéoplasiques (génétique)</term>
<term>Souris (MeSH)</term>
<term>Sulfonamides (pharmacologie)</term>
<term>Transduction du signal (effets des médicaments et des substances chimiques)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Amyloid Precursor Protein Secretases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Amyloid Precursor Protein Secretases</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Myeloid Cell Leukemia Sequence 1 Protein</term>
<term>Receptor, Notch1</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Aniline Compounds</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Leucémie-lymphome lymphoblastique à précurseurs T</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Amyloid precursor protein secretases</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term>
<term>Cell Proliferation</term>
<term>Drug Resistance, Neoplasm</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Apoptose</term>
<term>Prolifération cellulaire</term>
<term>Résistance aux médicaments antinéoplasiques</term>
<term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Drug Resistance, Neoplasm</term>
<term>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Amyloid precursor protein secretases</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs T</term>
<term>Protéine Mcl-1</term>
<term>Récepteur Notch1</term>
<term>Résistance aux médicaments antinéoplasiques</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Dérivés de l'aniline</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Leucémie-lymphome lymphoblastique à précurseurs T</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Heterografts</term>
<term>Humans</term>
<term>Mice</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Humains</term>
<term>Hétérogreffes</term>
<term>Lignée cellulaire tumorale</term>
<term>Souris</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p><b>PURPOSE</b>
</p>
<p>Effective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>EXPERIMENTAL DESIGN</b>
</p>
<p>We performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both </p>
</div>
<div type="abstract" xml:lang="en"><p><b>RESULTS</b>
</p>
<p>We found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax </p>
</div>
<div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b>
</p>
<p>Our results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.</p>
</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30224339</PMID>
<DateCompleted><Year>2020</Year>
<Month>02</Month>
<Day>26</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>03</Month>
<Day>09</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">1078-0432</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>25</Volume>
<Issue>1</Issue>
<PubDate><Year>2019</Year>
<Month>01</Month>
<Day>01</Day>
</PubDate>
</JournalIssue>
<Title>Clinical cancer research : an official journal of the American Association for Cancer Research</Title>
<ISOAbbreviation>Clin Cancer Res</ISOAbbreviation>
</Journal>
<ArticleTitle>NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.</ArticleTitle>
<Pagination><MedlinePgn>312-324</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1158/1078-0432.CCR-18-0867</ELocationID>
<Abstract><AbstractText Label="PURPOSE">Effective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL.</AbstractText>
<AbstractText Label="EXPERIMENTAL DESIGN">We performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both <i>in vitro</i>
 experiments and <i>in vivo</i>
 studies on patient-derived xenograft models.</AbstractText>
<AbstractText Label="RESULTS">We found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax <i>in vitro</i>
 and leads to tumor regressions <i>in vivo</i>
.</AbstractText>
<AbstractText Label="CONCLUSIONS">Our results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.</AbstractText>
<CopyrightInformation>©2018 American Association for Cancer Research.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y" EqualContrib="Y"><LastName>Dastur</LastName>
<ForeName>Anahita</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y" EqualContrib="Y"><LastName>Choi</LastName>
<ForeName>AHyun</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Costa</LastName>
<ForeName>Carlotta</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yin</LastName>
<ForeName>Xunqin</ForeName>
<Initials>X</Initials>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Williams</LastName>
<ForeName>August</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>McClanaghan</LastName>
<ForeName>Joseph</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Greenberg</LastName>
<ForeName>Max</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Roderick</LastName>
<ForeName>Justine</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Patel</LastName>
<ForeName>Neha U</ForeName>
<Initials>NU</Initials>
<AffiliationInfo><Affiliation>VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Boisvert</LastName>
<ForeName>Jessica</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>McDermott</LastName>
<ForeName>Ultan</ForeName>
<Initials>U</Initials>
<AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Garnett</LastName>
<ForeName>Mathew J</ForeName>
<Initials>MJ</Initials>
<AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Almenara</LastName>
<ForeName>Jorge</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Anatomic Pathology, Virginia Commonwealth University, Richmond, Virginia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Grant</LastName>
<ForeName>Steven</ForeName>
<Initials>S</Initials>
<Identifier Source="ORCID">0000-0003-4452-9320</Identifier>
<AffiliationInfo><Affiliation>Departments of Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, The Institute for Molecular Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rizzo</LastName>
<ForeName>Kathryn</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Department of Anatomic Pathology, Virginia Commonwealth University, Richmond, Virginia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Engelman</LastName>
<ForeName>Jeffrey A</ForeName>
<Initials>JA</Initials>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medicine, Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kelliher</LastName>
<ForeName>Michelle</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Faber</LastName>
<ForeName>Anthony C</ForeName>
<Initials>AC</Initials>
<AffiliationInfo><Affiliation>VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Benes</LastName>
<ForeName>Cyril H</ForeName>
<Initials>CH</Initials>
<Identifier Source="ORCID">0000-0002-8751-9707</Identifier>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts. cbenes@mgh.harvard.edu.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medicine, Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>R01 CA205607</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 CA096899</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 CA167708</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>102696</GrantID>
<Acronym>WT_</Acronym>
<Agency>Wellcome Trust</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>R01 CA140594</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 CA215610</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>086357</GrantID>
<Acronym>WT_</Acronym>
<Agency>Wellcome Trust</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><Agency>Wellcome Trust</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>K22 CA175276</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
</GrantList>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2018</Year>
<Month>09</Month>
<Day>17</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Clin Cancer Res</MedlineTA>
<NlmUniqueID>9502500</NlmUniqueID>
<ISSNLinking>1078-0432</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000814">Aniline Compounds</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C579095">MCL1 protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D064549">Myeloid Cell Leukemia Sequence 1 Protein</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C497761">NOTCH1 protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D051881">Receptor, Notch1</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D013449">Sulfonamides</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 3.4.-</RegistryNumber>
<NameOfSubstance UI="D053829">Amyloid Precursor Protein Secretases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>XKJ5VVK2WD</RegistryNumber>
<NameOfSubstance UI="C528561">navitoclax</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D053829" MajorTopicYN="N">Amyloid Precursor Protein Secretases</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000814" MajorTopicYN="N">Aniline Compounds</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017209" MajorTopicYN="N">Apoptosis</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D049109" MajorTopicYN="N">Cell Proliferation</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D019008" MajorTopicYN="N">Drug Resistance, Neoplasm</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D064593" MajorTopicYN="N">Heterografts</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D064549" MajorTopicYN="N">Myeloid Cell Leukemia Sequence 1 Protein</DescriptorName>
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   |texte=   NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.
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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

NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.

NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.

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