RapamycinFungusV1, Main, Exploration, bibRecord, 000360

Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition.

Identifieur interne : 000360 ( Main/Exploration ); précédent : 000359; suivant : 000361

Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition.

Auteurs : Kara M. Ruicci [Canada] ; Paul Plantinga [Canada] ; Nicole Pinto [Canada] ; Mohammed I. Khan [Canada] ; William Stecho [Canada] ; Sandeep S. Dhaliwal [Canada] ; John Yoo [Canada] ; Kevin Fung [Canada] ; Danielle Macneil [Canada] ; Joe S. Mymryk [Canada] ; John W. Barrett [Canada] ; Christopher J. Howlett [Canada] ; Anthony C. Nichols [Canada]

Source :

Molecular oncology [ 1878-0261 ] ; 2019.

RBID : pubmed:31393061

Descripteurs français

English descriptors

KwdEn :
- Antineoplastic Agents (pharmacology), CRISPR-Cas Systems (MeSH), Cell Line, Tumor (MeSH), Cisplatin (pharmacology), Erlotinib Hydrochloride (pharmacology), Head and Neck Neoplasms (drug therapy), Head and Neck Neoplasms (genetics), Head and Neck Neoplasms (metabolism), Humans (MeSH), Mechanistic Target of Rapamycin Complex 2 (genetics), Mechanistic Target of Rapamycin Complex 2 (metabolism), Phosphatidylinositol 3-Kinases (metabolism), Phosphoinositide-3 Kinase Inhibitors (pharmacology), Rapamycin-Insensitive Companion of mTOR Protein (genetics), Rapamycin-Insensitive Companion of mTOR Protein (metabolism), Squamous Cell Carcinoma of Head and Neck (drug therapy), Squamous Cell Carcinoma of Head and Neck (genetics), Squamous Cell Carcinoma of Head and Neck (metabolism).
MESH :
- chemical , genetics : Mechanistic Target of Rapamycin Complex 2, Rapamycin-Insensitive Companion of mTOR Protein.
- chemical , metabolism : Mechanistic Target of Rapamycin Complex 2, Rapamycin-Insensitive Companion of mTOR Protein.
- chemical , pharmacology : Antineoplastic Agents, Cisplatin, Erlotinib Hydrochloride, Phosphoinositide-3 Kinase Inhibitors.
- drug therapy : Head and Neck Neoplasms, Squamous Cell Carcinoma of Head and Neck.
- genetics : Head and Neck Neoplasms, Squamous Cell Carcinoma of Head and Neck.
- metabolism : Head and Neck Neoplasms, Phosphatidylinositol 3-Kinases, Squamous Cell Carcinoma of Head and Neck.
- CRISPR-Cas Systems, Cell Line, Tumor, Humans.

Abstract

Phosphoinositide 3-kinase (PI3K) is aberrantly activated in head and neck squamous cell carcinomas (HNSCC) and plays a pivotal role in tumorigenesis by driving Akt signaling, leading to cell survival and proliferation. Phosphorylation of Akt Thr308 by PI3K-PDK1 and Akt Ser473 by mammalian target of rapamycin complex 2 (mTORC2) activates Akt. Targeted inhibition of PI3K is a major area of preclinical and clinical investigation as it reduces Akt Thr308 phosphorylation, suppressing downstream mTORC1 activity. However, inhibition of mTORC1 releases feedback inhibition of mTORC2, resulting in a resurgence of Akt activation mediated by mTORC2. While the role of PI3K-activated Akt signaling is well established in HNSCC, the significance of mTORC2-driven Akt signaling has not been thoroughly examined. Here we explore the expression and function of mTORC2 and its obligate subunit RICTOR in HNSCC primary tumors and cell lines. We find RICTOR to be overexpressed in a subset of HNSCC tumors, including those with PIK3CA or EGFR gene amplifications. Whereas overexpression of RICTOR reduced susceptibility of HNSCC tumor cells to PI3K inhibition, genetic ablation of RICTOR using CRISPR/Cas9 sensitized cells to PI3K inhibition, as well as to EGFR inhibition and cisplatin treatment. Further, mTORC2 disruption led to reduced viability and colony forming abilities of HNSCC cells relative to their parental lines and induced loss of both activating Akt phosphorylation modifications (Thr308 and Ser473). Taken together, our findings establish RICTOR/mTORC2 as a critical oncogenic complex in HNSCC and rationalize the development of an mTORC2-specific inhibitor for use in HNSCC, either combined with agents already under investigation, or as an independent therapy.

DOI: 10.1002/1878-0261.12558
PubMed: 31393061
PubMed Central: PMC6763779

Affiliations:

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

to stream Main, to step Corpus: 000214
to stream Main, to step Curation: 000214

Le document en format XML

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<author><name sortKey="Dhaliwal, Sandeep S" sort="Dhaliwal, Sandeep S" uniqKey="Dhaliwal S" first="Sandeep S" last="Dhaliwal">Sandeep S. Dhaliwal</name>
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<author><name sortKey="Fung, Kevin" sort="Fung, Kevin" uniqKey="Fung K" first="Kevin" last="Fung">Kevin Fung</name>
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<author><name sortKey="Mymryk, Joe S" sort="Mymryk, Joe S" uniqKey="Mymryk J" first="Joe S" last="Mymryk">Joe S. Mymryk</name>
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<affiliation wicri:level="3"><nlm:affiliation>Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
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<author><name sortKey="Barrett, John W" sort="Barrett, John W" uniqKey="Barrett J" first="John W" last="Barrett">John W. Barrett</name>
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<author><name sortKey="Howlett, Christopher J" sort="Howlett, Christopher J" uniqKey="Howlett C" first="Christopher J" last="Howlett">Christopher J. Howlett</name>
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<author><name sortKey="Nichols, Anthony C" sort="Nichols, Anthony C" uniqKey="Nichols A" first="Anthony C" last="Nichols">Anthony C. Nichols</name>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition.</title>
<author><name sortKey="Ruicci, Kara M" sort="Ruicci, Kara M" uniqKey="Ruicci K" first="Kara M" last="Ruicci">Kara M. Ruicci</name>
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<author><name sortKey="Plantinga, Paul" sort="Plantinga, Paul" uniqKey="Plantinga P" first="Paul" last="Plantinga">Paul Plantinga</name>
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<author><name sortKey="Pinto, Nicole" sort="Pinto, Nicole" uniqKey="Pinto N" first="Nicole" last="Pinto">Nicole Pinto</name>
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<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
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<author><name sortKey="Khan, Mohammed I" sort="Khan, Mohammed I" uniqKey="Khan M" first="Mohammed I" last="Khan">Mohammed I. Khan</name>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
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<region type="country">Angleterre</region>
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<author><name sortKey="Stecho, William" sort="Stecho, William" uniqKey="Stecho W" first="William" last="Stecho">William Stecho</name>
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<author><name sortKey="Dhaliwal, Sandeep S" sort="Dhaliwal, Sandeep S" uniqKey="Dhaliwal S" first="Sandeep S" last="Dhaliwal">Sandeep S. Dhaliwal</name>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
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<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
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<author><name sortKey="Yoo, John" sort="Yoo, John" uniqKey="Yoo J" first="John" last="Yoo">John Yoo</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Fung, Kevin" sort="Fung, Kevin" uniqKey="Fung K" first="Kevin" last="Fung">Kevin Fung</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Macneil, Danielle" sort="Macneil, Danielle" uniqKey="Macneil D" first="Danielle" last="Macneil">Danielle Macneil</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mymryk, Joe S" sort="Mymryk, Joe S" uniqKey="Mymryk J" first="Joe S" last="Mymryk">Joe S. Mymryk</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:affiliation>Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Barrett, John W" sort="Barrett, John W" uniqKey="Barrett J" first="John W" last="Barrett">John W. Barrett</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Howlett, Christopher J" sort="Howlett, Christopher J" uniqKey="Howlett C" first="Christopher J" last="Howlett">Christopher J. Howlett</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nichols, Anthony C" sort="Nichols, Anthony C" uniqKey="Nichols A" first="Anthony C" last="Nichols">Anthony C. Nichols</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Molecular oncology</title>
<idno type="eISSN">1878-0261</idno>
<imprint><date when="2019" type="published">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antineoplastic Agents (pharmacology)</term>
<term>CRISPR-Cas Systems (MeSH)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Cisplatin (pharmacology)</term>
<term>Erlotinib Hydrochloride (pharmacology)</term>
<term>Head and Neck Neoplasms (drug therapy)</term>
<term>Head and Neck Neoplasms (genetics)</term>
<term>Head and Neck Neoplasms (metabolism)</term>
<term>Humans (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 2 (genetics)</term>
<term>Mechanistic Target of Rapamycin Complex 2 (metabolism)</term>
<term>Phosphatidylinositol 3-Kinases (metabolism)</term>
<term>Phosphoinositide-3 Kinase Inhibitors (pharmacology)</term>
<term>Rapamycin-Insensitive Companion of mTOR Protein (genetics)</term>
<term>Rapamycin-Insensitive Companion of mTOR Protein (metabolism)</term>
<term>Squamous Cell Carcinoma of Head and Neck (drug therapy)</term>
<term>Squamous Cell Carcinoma of Head and Neck (genetics)</term>
<term>Squamous Cell Carcinoma of Head and Neck (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Antinéoplasiques (pharmacologie)</term>
<term>Carcinome épidermoïde de la tête et du cou (génétique)</term>
<term>Carcinome épidermoïde de la tête et du cou (métabolisme)</term>
<term>Carcinome épidermoïde de la tête et du cou (traitement médicamenteux)</term>
<term>Chlorhydrate d'erlotinib (pharmacologie)</term>
<term>Cisplatine (pharmacologie)</term>
<term>Compagnon de mTOR insensible à la rapamycine (génétique)</term>
<term>Compagnon de mTOR insensible à la rapamycine (métabolisme)</term>
<term>Complexe-2 cible mécanistique de la rapamycine (génétique)</term>
<term>Complexe-2 cible mécanistique de la rapamycine (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Phosphatidylinositol 3-kinases (métabolisme)</term>
<term>Systèmes CRISPR-Cas (MeSH)</term>
<term>Tumeurs de la tête et du cou (génétique)</term>
<term>Tumeurs de la tête et du cou (métabolisme)</term>
<term>Tumeurs de la tête et du cou (traitement médicamenteux)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Mechanistic Target of Rapamycin Complex 2</term>
<term>Rapamycin-Insensitive Companion of mTOR Protein</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Mechanistic Target of Rapamycin Complex 2</term>
<term>Rapamycin-Insensitive Companion of mTOR Protein</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Cisplatin</term>
<term>Erlotinib Hydrochloride</term>
<term>Phosphoinositide-3 Kinase Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Head and Neck Neoplasms</term>
<term>Squamous Cell Carcinoma of Head and Neck</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Head and Neck Neoplasms</term>
<term>Squamous Cell Carcinoma of Head and Neck</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Carcinome épidermoïde de la tête et du cou</term>
<term>Compagnon de mTOR insensible à la rapamycine</term>
<term>Complexe-2 cible mécanistique de la rapamycine</term>
<term>Tumeurs de la tête et du cou</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Head and Neck Neoplasms</term>
<term>Phosphatidylinositol 3-Kinases</term>
<term>Squamous Cell Carcinoma of Head and Neck</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Carcinome épidermoïde de la tête et du cou</term>
<term>Compagnon de mTOR insensible à la rapamycine</term>
<term>Complexe-2 cible mécanistique de la rapamycine</term>
<term>Phosphatidylinositol 3-kinases</term>
<term>Tumeurs de la tête et du cou</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term>
<term>Chlorhydrate d'erlotinib</term>
<term>Cisplatine</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome épidermoïde de la tête et du cou</term>
<term>Tumeurs de la tête et du cou</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>CRISPR-Cas Systems</term>
<term>Cell Line, Tumor</term>
<term>Humans</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Systèmes CRISPR-Cas</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Phosphoinositide 3-kinase (PI3K) is aberrantly activated in head and neck squamous cell carcinomas (HNSCC) and plays a pivotal role in tumorigenesis by driving Akt signaling, leading to cell survival and proliferation. Phosphorylation of Akt Thr308 by PI3K-PDK1 and Akt Ser473 by mammalian target of rapamycin complex 2 (mTORC2) activates Akt. Targeted inhibition of PI3K is a major area of preclinical and clinical investigation as it reduces Akt Thr308 phosphorylation, suppressing downstream mTORC1 activity. However, inhibition of mTORC1 releases feedback inhibition of mTORC2, resulting in a resurgence of Akt activation mediated by mTORC2. While the role of PI3K-activated Akt signaling is well established in HNSCC, the significance of mTORC2-driven Akt signaling has not been thoroughly examined. Here we explore the expression and function of mTORC2 and its obligate subunit RICTOR in HNSCC primary tumors and cell lines. We find RICTOR to be overexpressed in a subset of HNSCC tumors, including those with PIK3CA or EGFR gene amplifications. Whereas overexpression of RICTOR reduced susceptibility of HNSCC tumor cells to PI3K inhibition, genetic ablation of RICTOR using CRISPR/Cas9 sensitized cells to PI3K inhibition, as well as to EGFR inhibition and cisplatin treatment. Further, mTORC2 disruption led to reduced viability and colony forming abilities of HNSCC cells relative to their parental lines and induced loss of both activating Akt phosphorylation modifications (Thr308 and Ser473). Taken together, our findings establish RICTOR/mTORC2 as a critical oncogenic complex in HNSCC and rationalize the development of an mTORC2-specific inhibitor for use in HNSCC, either combined with agents already under investigation, or as an independent therapy.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31393061</PMID>
<DateCompleted><Year>2020</Year>
<Month>06</Month>
<Day>29</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>06</Month>
<Day>29</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1878-0261</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>13</Volume>
<Issue>10</Issue>
<PubDate><Year>2019</Year>
<Month>10</Month>
</PubDate>
</JournalIssue>
<Title>Molecular oncology</Title>
<ISOAbbreviation>Mol Oncol</ISOAbbreviation>
</Journal>
<ArticleTitle>Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition.</ArticleTitle>
<Pagination><MedlinePgn>2160-2177</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1002/1878-0261.12558</ELocationID>
<Abstract><AbstractText>Phosphoinositide 3-kinase (PI3K) is aberrantly activated in head and neck squamous cell carcinomas (HNSCC) and plays a pivotal role in tumorigenesis by driving Akt signaling, leading to cell survival and proliferation. Phosphorylation of Akt Thr308 by PI3K-PDK1 and Akt Ser473 by mammalian target of rapamycin complex 2 (mTORC2) activates Akt. Targeted inhibition of PI3K is a major area of preclinical and clinical investigation as it reduces Akt Thr308 phosphorylation, suppressing downstream mTORC1 activity. However, inhibition of mTORC1 releases feedback inhibition of mTORC2, resulting in a resurgence of Akt activation mediated by mTORC2. While the role of PI3K-activated Akt signaling is well established in HNSCC, the significance of mTORC2-driven Akt signaling has not been thoroughly examined. Here we explore the expression and function of mTORC2 and its obligate subunit RICTOR in HNSCC primary tumors and cell lines. We find RICTOR to be overexpressed in a subset of HNSCC tumors, including those with PIK3CA or EGFR gene amplifications. Whereas overexpression of RICTOR reduced susceptibility of HNSCC tumor cells to PI3K inhibition, genetic ablation of RICTOR using CRISPR/Cas9 sensitized cells to PI3K inhibition, as well as to EGFR inhibition and cisplatin treatment. Further, mTORC2 disruption led to reduced viability and colony forming abilities of HNSCC cells relative to their parental lines and induced loss of both activating Akt phosphorylation modifications (Thr308 and Ser473). Taken together, our findings establish RICTOR/mTORC2 as a critical oncogenic complex in HNSCC and rationalize the development of an mTORC2-specific inhibitor for use in HNSCC, either combined with agents already under investigation, or as an independent therapy.</AbstractText>
<CopyrightInformation>© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ruicci</LastName>
<ForeName>Kara M</ForeName>
<Initials>KM</Initials>
<Identifier Source="ORCID">0000-0003-2691-3505</Identifier>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Plantinga</LastName>
<ForeName>Paul</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pinto</LastName>
<ForeName>Nicole</ForeName>
<Initials>N</Initials>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Khan</LastName>
<ForeName>Mohammed I</ForeName>
<Initials>MI</Initials>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Stecho</LastName>
<ForeName>William</ForeName>
<Initials>W</Initials>
<AffiliationInfo><Affiliation>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Dhaliwal</LastName>
<ForeName>Sandeep S</ForeName>
<Initials>SS</Initials>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yoo</LastName>
<ForeName>John</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Fung</LastName>
<ForeName>Kevin</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>MacNeil</LastName>
<ForeName>Danielle</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mymryk</LastName>
<ForeName>Joe S</ForeName>
<Initials>JS</Initials>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Barrett</LastName>
<ForeName>John W</ForeName>
<Initials>JW</Initials>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Howlett</LastName>
<ForeName>Christopher J</ForeName>
<Initials>CJ</Initials>
<AffiliationInfo><Affiliation>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Nichols</LastName>
<ForeName>Anthony C</ForeName>
<Initials>AC</Initials>
<AffiliationInfo><Affiliation>Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Canada.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>MOP 340674</GrantID>
<Agency>Canadian Institutes for Health Research (CIHR)</Agency>
<Country>International</Country>
</Grant>
</GrantList>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2019</Year>
<Month>08</Month>
<Day>28</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Mol Oncol</MedlineTA>
<NlmUniqueID>101308230</NlmUniqueID>
<ISSNLinking>1574-7891</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000970">Antineoplastic Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000081082">Phosphoinositide-3 Kinase Inhibitors</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000076226">Rapamycin-Insensitive Companion of mTOR Protein</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>DA87705X9K</RegistryNumber>
<NameOfSubstance UI="D000069347">Erlotinib Hydrochloride</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="D000076225">Mechanistic Target of Rapamycin Complex 2</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>Q20Q21Q62J</RegistryNumber>
<NameOfSubstance UI="D002945">Cisplatin</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<CommentsCorrectionsList><CommentsCorrections RefType="ErratumIn"><RefSource>Mol Oncol. 2020 Jan;14(1):230-231</RefSource>
<PMID Version="1">31804024</PMID>
</CommentsCorrections>
</CommentsCorrectionsList>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000970" MajorTopicYN="N">Antineoplastic Agents</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D064113" MajorTopicYN="N">CRISPR-Cas Systems</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002945" MajorTopicYN="N">Cisplatin</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000069347" MajorTopicYN="N">Erlotinib Hydrochloride</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006258" MajorTopicYN="N">Head and Neck Neoplasms</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000076225" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 2</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D019869" MajorTopicYN="N">Phosphatidylinositol 3-Kinases</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000081082" MajorTopicYN="N">Phosphoinositide-3 Kinase Inhibitors</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
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	Serveur d'exploration sur la rapamycine et les champignons
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Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition.

Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition.

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