RapamycinFungusV1, Main, Exploration, bibRecord, 000C71

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.

Identifieur interne : 000C71 ( Main/Exploration ); précédent : 000C70; suivant : 000C72

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.

Auteurs : Hung Huynh [Singapour] ; Huai-Xiang Hao [États-Unis] ; Stephen L. Chan [République populaire de Chine] ; David Chen [États-Unis] ; Richard Ong [Singapour] ; Khee Chee Soo [Singapour] ; Panisa Pochanard [États-Unis] ; David Yang [États-Unis] ; David Ruddy [États-Unis] ; Manway Liu [États-Unis] ; Adnan Derti [États-Unis] ; Marissa N. Balak [États-Unis] ; Michael R. Palmer [États-Unis] ; Yan Wang [États-Unis] ; Benjamin H. Lee [États-Unis] ; Dalila Sellami [États-Unis] ; Andrew X. Zhu [États-Unis] ; Robert Schlegel [États-Unis] ; Alan Huang [États-Unis]

Source :

Molecular cancer therapeutics [ 1538-8514 ] ; 2015.

RBID : pubmed:25724664

Descripteurs français

KwdFr :
- Animaux (MeSH), Antinéoplasiques (usage thérapeutique), Carcinome hépatocellulaire (génétique), Carcinome hépatocellulaire (traitement médicamenteux), Carcinome hépatocellulaire (virologie), Complexe-1 cible mécanistique de la rapamycine (MeSH), Complexes multiprotéiques (antagonistes et inhibiteurs), Humains (MeSH), Hépatite B (génétique), Hépatite B (épidémiologie), Lignée cellulaire tumorale (MeSH), Mutation (MeSH), Mâle (MeSH), Population d'origine asiatique (génétique), Protéine-2 du complexe de la sclérose tubéreuse (MeSH), Protéines suppresseurs de tumeurs (génétique), Résultat thérapeutique (MeSH), Souris (MeSH), Sérine-thréonine kinases TOR (antagonistes et inhibiteurs), Transduction du signal (effets des médicaments et des substances chimiques), Tumeurs du foie (génétique), Tumeurs du foie (traitement médicamenteux), Tumeurs du foie (virologie), Évérolimus (usage thérapeutique).
MESH :
- antagonistes et inhibiteurs : Complexes multiprotéiques, Sérine-thréonine kinases TOR.
- effets des médicaments et des substances chimiques : Transduction du signal.
- génétique : Carcinome hépatocellulaire, Hépatite B, Population d'origine asiatique, Protéines suppresseurs de tumeurs, Tumeurs du foie.
- traitement médicamenteux : Carcinome hépatocellulaire, Tumeurs du foie.
- usage thérapeutique : Antinéoplasiques, Évérolimus.
- virologie : Carcinome hépatocellulaire, Tumeurs du foie.
- épidémiologie : Hépatite B.
- Animaux, Complexe-1 cible mécanistique de la rapamycine, Humains, Lignée cellulaire tumorale, Mutation, Mâle, Protéine-2 du complexe de la sclérose tubéreuse, Résultat thérapeutique, Souris.

English descriptors

KwdEn :
- Animals (MeSH), Antineoplastic Agents (therapeutic use), Asian Continental Ancestry Group (genetics), Carcinoma, Hepatocellular (drug therapy), Carcinoma, Hepatocellular (genetics), Carcinoma, Hepatocellular (virology), Cell Line, Tumor (MeSH), Everolimus (therapeutic use), Hepatitis B (epidemiology), Hepatitis B (genetics), Humans (MeSH), Liver Neoplasms (drug therapy), Liver Neoplasms (genetics), Liver Neoplasms (virology), Male (MeSH), Mechanistic Target of Rapamycin Complex 1 (MeSH), Mice (MeSH), Multiprotein Complexes (antagonists & inhibitors), Mutation (MeSH), Signal Transduction (drug effects), TOR Serine-Threonine Kinases (antagonists & inhibitors), Treatment Outcome (MeSH), Tuberous Sclerosis Complex 2 Protein (MeSH), Tumor Suppressor Proteins (genetics).
MESH :
- chemical , antagonists & inhibitors : Multiprotein Complexes, TOR Serine-Threonine Kinases.
- chemical , genetics : Tumor Suppressor Proteins.
- chemical , therapeutic use : Antineoplastic Agents, Everolimus.
- drug effects : Signal Transduction.
- drug therapy : Carcinoma, Hepatocellular, Liver Neoplasms.
- epidemiology : Hepatitis B.
- genetics : Asian Continental Ancestry Group, Carcinoma, Hepatocellular, Hepatitis B, Liver Neoplasms.
- virology : Carcinoma, Hepatocellular, Liver Neoplasms.
- Animals, Cell Line, Tumor, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Mutation, Treatment Outcome, Tuberous Sclerosis Complex 2 Protein.

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV(+) HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients.

DOI: 10.1158/1535-7163.MCT-14-0768
PubMed: 25724664

Affiliations:

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

to stream Main, to step Corpus: 000C99
to stream Main, to step Curation: 000C99

Le document en format XML

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<author><name sortKey="Ruddy, David" sort="Ruddy, David" uniqKey="Ruddy D" first="David" last="Ruddy">David Ruddy</name>
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<author><name sortKey="Liu, Manway" sort="Liu, Manway" uniqKey="Liu M" first="Manway" last="Liu">Manway Liu</name>
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<author><name sortKey="Balak, Marissa N" sort="Balak, Marissa N" uniqKey="Balak M" first="Marissa N" last="Balak">Marissa N. Balak</name>
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<author><name sortKey="Palmer, Michael R" sort="Palmer, Michael R" uniqKey="Palmer M" first="Michael R" last="Palmer">Michael R. Palmer</name>
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<author><name sortKey="Wang, Yan" sort="Wang, Yan" uniqKey="Wang Y" first="Yan" last="Wang">Yan Wang</name>
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<author><name sortKey="Lee, Benjamin H" sort="Lee, Benjamin H" uniqKey="Lee B" first="Benjamin H" last="Lee">Benjamin H. Lee</name>
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</affiliation>
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<author><name sortKey="Zhu, Andrew X" sort="Zhu, Andrew X" uniqKey="Zhu A" first="Andrew X" last="Zhu">Andrew X. Zhu</name>
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<author><name sortKey="Schlegel, Robert" sort="Schlegel, Robert" uniqKey="Schlegel R" first="Robert" last="Schlegel">Robert Schlegel</name>
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</placeName>
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</affiliation>
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<author><name sortKey="Huang, Alan" sort="Huang, Alan" uniqKey="Huang A" first="Alan" last="Huang">Alan Huang</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.</title>
<author><name sortKey="Huynh, Hung" sort="Huynh, Hung" uniqKey="Huynh H" first="Hung" last="Huynh">Hung Huynh</name>
<affiliation wicri:level="1"><nlm:affiliation>Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore. alan.huang@novartis.com cmrhth@nccs.com.sg.</nlm:affiliation>
<country xml:lang="fr">Singapour</country>
<wicri:regionArea>Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre</wicri:regionArea>
<wicri:noRegion>National Cancer Centre</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hao, Huai Xiang" sort="Hao, Huai Xiang" uniqKey="Hao H" first="Huai-Xiang" last="Hao">Huai-Xiang Hao</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Chan, Stephen L" sort="Chan, Stephen L" uniqKey="Chan S" first="Stephen L" last="Chan">Stephen L. Chan</name>
<affiliation wicri:level="4"><nlm:affiliation>State Key Laboratory in Oncology in South China, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>State Key Laboratory in Oncology in South China, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong</wicri:regionArea>
<orgName type="university">Université chinoise de Hong Kong</orgName>
<placeName><settlement type="city">Sha Tin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Chen, David" sort="Chen, David" uniqKey="Chen D" first="David" last="Chen">David Chen</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">New Jersey</region>
</placeName>
<wicri:cityArea>Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Ong, Richard" sort="Ong, Richard" uniqKey="Ong R" first="Richard" last="Ong">Richard Ong</name>
<affiliation wicri:level="1"><nlm:affiliation>Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.</nlm:affiliation>
<country xml:lang="fr">Singapour</country>
<wicri:regionArea>Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre</wicri:regionArea>
<wicri:noRegion>National Cancer Centre</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Soo, Khee Chee" sort="Soo, Khee Chee" uniqKey="Soo K" first="Khee Chee" last="Soo">Khee Chee Soo</name>
<affiliation wicri:level="1"><nlm:affiliation>Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.</nlm:affiliation>
<country xml:lang="fr">Singapour</country>
<wicri:regionArea>Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre</wicri:regionArea>
<wicri:noRegion>National Cancer Centre</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Pochanard, Panisa" sort="Pochanard, Panisa" uniqKey="Pochanard P" first="Panisa" last="Pochanard">Panisa Pochanard</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Yang, David" sort="Yang, David" uniqKey="Yang D" first="David" last="Yang">David Yang</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Ruddy, David" sort="Ruddy, David" uniqKey="Ruddy D" first="David" last="Ruddy">David Ruddy</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Liu, Manway" sort="Liu, Manway" uniqKey="Liu M" first="Manway" last="Liu">Manway Liu</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Derti, Adnan" sort="Derti, Adnan" uniqKey="Derti A" first="Adnan" last="Derti">Adnan Derti</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Balak, Marissa N" sort="Balak, Marissa N" uniqKey="Balak M" first="Marissa N" last="Balak">Marissa N. Balak</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Palmer, Michael R" sort="Palmer, Michael R" uniqKey="Palmer M" first="Michael R" last="Palmer">Michael R. Palmer</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Wang, Yan" sort="Wang, Yan" uniqKey="Wang Y" first="Yan" last="Wang">Yan Wang</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Lee, Benjamin H" sort="Lee, Benjamin H" uniqKey="Lee B" first="Benjamin H" last="Lee">Benjamin H. Lee</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
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</affiliation>
</author>
<author><name sortKey="Sellami, Dalila" sort="Sellami, Dalila" uniqKey="Sellami D" first="Dalila" last="Sellami">Dalila Sellami</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">New Jersey</region>
</placeName>
<wicri:cityArea>Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Zhu, Andrew X" sort="Zhu, Andrew X" uniqKey="Zhu A" first="Andrew X" last="Zhu">Andrew X. Zhu</name>
<affiliation wicri:level="2"><nlm:affiliation>Massachusetts General Hospital Cancer Center, 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, Harvard Medical School, Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Schlegel, Robert" sort="Schlegel, Robert" uniqKey="Schlegel R" first="Robert" last="Schlegel">Robert Schlegel</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Huang, Alan" sort="Huang, Alan" uniqKey="Huang A" first="Alan" last="Huang">Alan Huang</name>
<affiliation wicri:level="2"><nlm:affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. alan.huang@novartis.com cmrhth@nccs.com.sg.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge</wicri:cityArea>
</affiliation>
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<series><title level="j">Molecular cancer therapeutics</title>
<idno type="eISSN">1538-8514</idno>
<imprint><date when="2015" type="published">2015</date>
</imprint>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term>
<term>Antineoplastic Agents (therapeutic use)</term>
<term>Asian Continental Ancestry Group (genetics)</term>
<term>Carcinoma, Hepatocellular (drug therapy)</term>
<term>Carcinoma, Hepatocellular (genetics)</term>
<term>Carcinoma, Hepatocellular (virology)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Everolimus (therapeutic use)</term>
<term>Hepatitis B (epidemiology)</term>
<term>Hepatitis B (genetics)</term>
<term>Humans (MeSH)</term>
<term>Liver Neoplasms (drug therapy)</term>
<term>Liver Neoplasms (genetics)</term>
<term>Liver Neoplasms (virology)</term>
<term>Male (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term>
<term>Mice (MeSH)</term>
<term>Multiprotein Complexes (antagonists & inhibitors)</term>
<term>Mutation (MeSH)</term>
<term>Signal Transduction (drug effects)</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
<term>Treatment Outcome (MeSH)</term>
<term>Tuberous Sclerosis Complex 2 Protein (MeSH)</term>
<term>Tumor Suppressor Proteins (genetics)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Antinéoplasiques (usage thérapeutique)</term>
<term>Carcinome hépatocellulaire (génétique)</term>
<term>Carcinome hépatocellulaire (traitement médicamenteux)</term>
<term>Carcinome hépatocellulaire (virologie)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term>
<term>Complexes multiprotéiques (antagonistes et inhibiteurs)</term>
<term>Humains (MeSH)</term>
<term>Hépatite B (génétique)</term>
<term>Hépatite B (épidémiologie)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Mutation (MeSH)</term>
<term>Mâle (MeSH)</term>
<term>Population d'origine asiatique (génétique)</term>
<term>Protéine-2 du complexe de la sclérose tubéreuse (MeSH)</term>
<term>Protéines suppresseurs de tumeurs (génétique)</term>
<term>Résultat thérapeutique (MeSH)</term>
<term>Souris (MeSH)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Transduction du signal (effets des médicaments et des substances chimiques)</term>
<term>Tumeurs du foie (génétique)</term>
<term>Tumeurs du foie (traitement médicamenteux)</term>
<term>Tumeurs du foie (virologie)</term>
<term>Évérolimus (usage thérapeutique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Multiprotein Complexes</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Tumor Suppressor Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Everolimus</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Complexes multiprotéiques</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Hepatocellular</term>
<term>Liver Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" qualifier="epidemiology" xml:lang="en"><term>Hepatitis B</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Asian Continental Ancestry Group</term>
<term>Carcinoma, Hepatocellular</term>
<term>Hepatitis B</term>
<term>Liver Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Carcinome hépatocellulaire</term>
<term>Hépatite B</term>
<term>Population d'origine asiatique</term>
<term>Protéines suppresseurs de tumeurs</term>
<term>Tumeurs du foie</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome hépatocellulaire</term>
<term>Tumeurs du foie</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Antinéoplasiques</term>
<term>Évérolimus</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Carcinome hépatocellulaire</term>
<term>Tumeurs du foie</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Carcinoma, Hepatocellular</term>
<term>Liver Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="épidémiologie" xml:lang="fr"><term>Hépatite B</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Humans</term>
<term>Male</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Mice</term>
<term>Mutation</term>
<term>Treatment Outcome</term>
<term>Tuberous Sclerosis Complex 2 Protein</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Mutation</term>
<term>Mâle</term>
<term>Protéine-2 du complexe de la sclérose tubéreuse</term>
<term>Résultat thérapeutique</term>
<term>Souris</term>
</keywords>
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<front><div type="abstract" xml:lang="en">Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV(+) HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25724664</PMID>
<DateCompleted><Year>2016</Year>
<Month>02</Month>
<Day>01</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>09</Month>
<Day>30</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1538-8514</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>14</Volume>
<Issue>5</Issue>
<PubDate><Year>2015</Year>
<Month>May</Month>
</PubDate>
</JournalIssue>
<Title>Molecular cancer therapeutics</Title>
<ISOAbbreviation>Mol Cancer Ther</ISOAbbreviation>
</Journal>
<ArticleTitle>Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.</ArticleTitle>
<Pagination><MedlinePgn>1224-35</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1158/1535-7163.MCT-14-0768</ELocationID>
<Abstract><AbstractText>Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV(+) HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients.</AbstractText>
<CopyrightInformation>©2015 American Association for Cancer Research.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Huynh</LastName>
<ForeName>Hung</ForeName>
<Initials>H</Initials>
<AffiliationInfo><Affiliation>Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore. alan.huang@novartis.com cmrhth@nccs.com.sg.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hao</LastName>
<ForeName>Huai-Xiang</ForeName>
<Initials>HX</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chan</LastName>
<ForeName>Stephen L</ForeName>
<Initials>SL</Initials>
<AffiliationInfo><Affiliation>State Key Laboratory in Oncology in South China, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, PR China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chen</LastName>
<ForeName>David</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ong</LastName>
<ForeName>Richard</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Soo</LastName>
<ForeName>Khee Chee</ForeName>
<Initials>KC</Initials>
<AffiliationInfo><Affiliation>Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pochanard</LastName>
<ForeName>Panisa</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yang</LastName>
<ForeName>David</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ruddy</LastName>
<ForeName>David</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Liu</LastName>
<ForeName>Manway</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Derti</LastName>
<ForeName>Adnan</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Balak</LastName>
<ForeName>Marissa N</ForeName>
<Initials>MN</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Palmer</LastName>
<ForeName>Michael R</ForeName>
<Initials>MR</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wang</LastName>
<ForeName>Yan</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lee</LastName>
<ForeName>Benjamin H</ForeName>
<Initials>BH</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sellami</LastName>
<ForeName>Dalila</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zhu</LastName>
<ForeName>Andrew X</ForeName>
<Initials>AX</Initials>
<AffiliationInfo><Affiliation>Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Schlegel</LastName>
<ForeName>Robert</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Huang</LastName>
<ForeName>Alan</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. alan.huang@novartis.com cmrhth@nccs.com.sg.</Affiliation>
</AffiliationInfo>
</Author>
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<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2015</Year>
<Month>02</Month>
<Day>27</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Mol Cancer Ther</MedlineTA>
<NlmUniqueID>101132535</NlmUniqueID>
<ISSNLinking>1535-7163</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000970">Antineoplastic Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D046912">Multiprotein Complexes</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C000624653">TSC2 protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C000624654">Tsc2 protein, mouse</NameOfSubstance>
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<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000077005">Tuberous Sclerosis Complex 2 Protein</NameOfSubstance>
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</MeshHeading>
<MeshHeading><DescriptorName UI="D000970" MajorTopicYN="N">Antineoplastic Agents</DescriptorName>
<QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D044466" MajorTopicYN="N">Asian Continental Ancestry Group</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
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<QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
</MeshHeading>
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<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
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</MeshHeading>
<MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName>
</MeshHeading>
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<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
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<MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName>
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<MeshHeading><DescriptorName UI="D000077005" MajorTopicYN="N">Tuberous Sclerosis Complex 2 Protein</DescriptorName>
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<MeshHeading><DescriptorName UI="D025521" MajorTopicYN="N">Tumor Suppressor Proteins</DescriptorName>
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<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2014</Year>
<Month>10</Month>
<Day>27</Day>
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<Month>02</Month>
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<affiliations><list><country><li>République populaire de Chine</li>
<li>Singapour</li>
<li>États-Unis</li>
</country>
<region><li>Massachusetts</li>
<li>New Jersey</li>
</region>
<settlement><li>Sha Tin</li>
</settlement>
<orgName><li>Université chinoise de Hong Kong</li>
</orgName>
</list>
<tree><country name="Singapour"><noRegion><name sortKey="Huynh, Hung" sort="Huynh, Hung" uniqKey="Huynh H" first="Hung" last="Huynh">Hung Huynh</name>
</noRegion>
<name sortKey="Ong, Richard" sort="Ong, Richard" uniqKey="Ong R" first="Richard" last="Ong">Richard Ong</name>
<name sortKey="Soo, Khee Chee" sort="Soo, Khee Chee" uniqKey="Soo K" first="Khee Chee" last="Soo">Khee Chee Soo</name>
</country>
<country name="États-Unis"><region name="Massachusetts"><name sortKey="Hao, Huai Xiang" sort="Hao, Huai Xiang" uniqKey="Hao H" first="Huai-Xiang" last="Hao">Huai-Xiang Hao</name>
</region>
<name sortKey="Balak, Marissa N" sort="Balak, Marissa N" uniqKey="Balak M" first="Marissa N" last="Balak">Marissa N. Balak</name>
<name sortKey="Chen, David" sort="Chen, David" uniqKey="Chen D" first="David" last="Chen">David Chen</name>
<name sortKey="Derti, Adnan" sort="Derti, Adnan" uniqKey="Derti A" first="Adnan" last="Derti">Adnan Derti</name>
<name sortKey="Huang, Alan" sort="Huang, Alan" uniqKey="Huang A" first="Alan" last="Huang">Alan Huang</name>
<name sortKey="Lee, Benjamin H" sort="Lee, Benjamin H" uniqKey="Lee B" first="Benjamin H" last="Lee">Benjamin H. Lee</name>
<name sortKey="Liu, Manway" sort="Liu, Manway" uniqKey="Liu M" first="Manway" last="Liu">Manway Liu</name>
<name sortKey="Palmer, Michael R" sort="Palmer, Michael R" uniqKey="Palmer M" first="Michael R" last="Palmer">Michael R. Palmer</name>
<name sortKey="Pochanard, Panisa" sort="Pochanard, Panisa" uniqKey="Pochanard P" first="Panisa" last="Pochanard">Panisa Pochanard</name>
<name sortKey="Ruddy, David" sort="Ruddy, David" uniqKey="Ruddy D" first="David" last="Ruddy">David Ruddy</name>
<name sortKey="Schlegel, Robert" sort="Schlegel, Robert" uniqKey="Schlegel R" first="Robert" last="Schlegel">Robert Schlegel</name>
<name sortKey="Sellami, Dalila" sort="Sellami, Dalila" uniqKey="Sellami D" first="Dalila" last="Sellami">Dalila Sellami</name>
<name sortKey="Wang, Yan" sort="Wang, Yan" uniqKey="Wang Y" first="Yan" last="Wang">Yan Wang</name>
<name sortKey="Yang, David" sort="Yang, David" uniqKey="Yang D" first="David" last="Yang">David Yang</name>
<name sortKey="Zhu, Andrew X" sort="Zhu, Andrew X" uniqKey="Zhu A" first="Andrew X" last="Zhu">Andrew X. Zhu</name>
</country>
<country name="République populaire de Chine"><noRegion><name sortKey="Chan, Stephen L" sort="Chan, Stephen L" uniqKey="Chan S" first="Stephen L" last="Chan">Stephen L. Chan</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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{{Explor lien
   |wiki=    Bois
   |area=    RapamycinFungusV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     pubmed:25724664
   |texte=   Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.
}}

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This area was generated with Dilib version V0.6.38.
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	Serveur d'exploration sur la rapamycine et les champignons
	Attention, ce site est en cours de développement ! Attention, site généré par des moyens informatiques à partir de corpus bruts. Les informations ne sont donc pas validées.

Serveur d'exploration sur la rapamycine et les champignons

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.

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