Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer.
Identifieur interne : 000135 ( Main/Exploration ); précédent : 000134; suivant : 000136Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer.
Auteurs : Allison S. Cohen [États-Unis] ; Ling Geng [États-Unis] ; Ping Zhao [États-Unis] ; Allie Fu [États-Unis] ; Michael L. Schulte [États-Unis] ; Ramona Graves-Deal [États-Unis] ; M Kay Washington [États-Unis] ; Jordan Berlin [États-Unis] ; Robert J. Coffey [États-Unis] ; H Charles Manning [États-Unis]Source :
- Translational oncology [ 1936-5233 ] ; 2020.
Abstract
Improving response to epidermal growth factor receptor (EGFR)-targeted therapies in patients with advanced wild-type (WT) RAS colorectal cancer (CRC) remains an unmet need. In this preclinical work, we evaluated a new therapeutic combination aimed at enhancing efficacy by targeting cancer cell metabolism in concert with EGFR. We hypothesized that combined blockade of glutamine metabolism and EGFR represents a promising treatment approach by targeting both the "fuel" and "signaling" components that these tumors need to survive. To explore this hypothesis, we combined CB-839, an inhibitor of glutaminase 1 (GLS1), the mitochondrial enzyme responsible for catalyzing conversion of glutamine to glutamate, with cetuximab, an EGFR-targeted monoclonal antibody in preclinical models of CRC. 2D and 3D in vitro assays were executed following treatment with either single agent or combination therapy. The combination of cetuximab with CB-839 resulted in reduced cell viability and demonstrated synergism in several cell lines. In vivo efficacy experiments were performed in cell-line xenograft models propagated in athymic nude mice. Tumor volumes were measured followed by immunohistochemical (IHC) analysis of proliferation (Ki67), mechanistic target of rapamycin (mTOR) signaling (pS6), and multiple mechanisms of cell death to annotate molecular determinants of response. In vivo, a significant reduction in tumor growth and reduced Ki67 and pS6 IHC staining were observed with combination therapy, which was accompanied by increased apoptosis and/or necrosis. The combination showed efficacy in cetuximab-sensitive as well as resistant models. In conclusion, this therapeutic combination represents a promising new precision medicine approach for patients with refractory metastatic WT RAS CRC.
DOI: 10.1016/j.tranon.2020.100828
PubMed: 32652471
PubMed Central: PMC7348062
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer.</title><author><name sortKey="Cohen, Allison S" sort="Cohen, Allison S" uniqKey="Cohen A" first="Allison S" last="Cohen">Allison S. Cohen</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Geng, Ling" sort="Geng, Ling" uniqKey="Geng L" first="Ling" last="Geng">Ling Geng</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Zhao, Ping" sort="Zhao, Ping" uniqKey="Zhao P" first="Ping" last="Zhao">Ping Zhao</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Fu, Allie" sort="Fu, Allie" uniqKey="Fu A" first="Allie" last="Fu">Allie Fu</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Schulte, Michael L" sort="Schulte, Michael L" uniqKey="Schulte M" first="Michael L" last="Schulte">Michael L. Schulte</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Graves Deal, Ramona" sort="Graves Deal, Ramona" uniqKey="Graves Deal R" first="Ramona" last="Graves-Deal">Ramona Graves-Deal</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Washington, M Kay" sort="Washington, M Kay" uniqKey="Washington M" first="M Kay" last="Washington">M Kay Washington</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, C-3322, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, C-3322, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Berlin, Jordan" sort="Berlin, Jordan" uniqKey="Berlin J" first="Jordan" last="Berlin">Jordan Berlin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Coffey, Robert J" sort="Coffey, Robert J" uniqKey="Coffey R" first="Robert J" last="Coffey">Robert J. Coffey</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States; Veterans Health Administration, Tennessee Valley Healthcare System, 1310 24th Avenue South, Nashville, TN 37212, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States; Veterans Health Administration, Tennessee Valley Healthcare System, 1310 24th Avenue South, Nashville, TN 37212</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Manning, H Charles" sort="Manning, H Charles" uniqKey="Manning H" first="H Charles" last="Manning">H Charles Manning</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States. Electronic address: henry.c.manning@vumc.org.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32652471</idno><idno type="pmid">32652471</idno><idno type="doi">10.1016/j.tranon.2020.100828</idno><idno type="pmc">PMC7348062</idno><idno type="wicri:Area/Main/Corpus">000044</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000044</idno><idno type="wicri:Area/Main/Curation">000044</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000044</idno><idno type="wicri:Area/Main/Exploration">000044</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer.</title><author><name sortKey="Cohen, Allison S" sort="Cohen, Allison S" uniqKey="Cohen A" first="Allison S" last="Cohen">Allison S. Cohen</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Geng, Ling" sort="Geng, Ling" uniqKey="Geng L" first="Ling" last="Geng">Ling Geng</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Zhao, Ping" sort="Zhao, Ping" uniqKey="Zhao P" first="Ping" last="Zhao">Ping Zhao</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Fu, Allie" sort="Fu, Allie" uniqKey="Fu A" first="Allie" last="Fu">Allie Fu</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Schulte, Michael L" sort="Schulte, Michael L" uniqKey="Schulte M" first="Michael L" last="Schulte">Michael L. Schulte</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Graves Deal, Ramona" sort="Graves Deal, Ramona" uniqKey="Graves Deal R" first="Ramona" last="Graves-Deal">Ramona Graves-Deal</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Washington, M Kay" sort="Washington, M Kay" uniqKey="Washington M" first="M Kay" last="Washington">M Kay Washington</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, C-3322, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, C-3322, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Berlin, Jordan" sort="Berlin, Jordan" uniqKey="Berlin J" first="Jordan" last="Berlin">Jordan Berlin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Coffey, Robert J" sort="Coffey, Robert J" uniqKey="Coffey R" first="Robert J" last="Coffey">Robert J. Coffey</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States; Veterans Health Administration, Tennessee Valley Healthcare System, 1310 24th Avenue South, Nashville, TN 37212, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States; Veterans Health Administration, Tennessee Valley Healthcare System, 1310 24th Avenue South, Nashville, TN 37212</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Manning, H Charles" sort="Manning, H Charles" uniqKey="Manning H" first="H Charles" last="Manning">H Charles Manning</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States. Electronic address: henry.c.manning@vumc.org.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author></analytic><series><title level="j">Translational oncology</title><idno type="ISSN">1936-5233</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Improving response to epidermal growth factor receptor (EGFR)-targeted therapies in patients with advanced wild-type (WT) RAS colorectal cancer (CRC) remains an unmet need. In this preclinical work, we evaluated a new therapeutic combination aimed at enhancing efficacy by targeting cancer cell metabolism in concert with EGFR. We hypothesized that combined blockade of glutamine metabolism and EGFR represents a promising treatment approach by targeting both the "fuel" and "signaling" components that these tumors need to survive. To explore this hypothesis, we combined CB-839, an inhibitor of glutaminase 1 (GLS1), the mitochondrial enzyme responsible for catalyzing conversion of glutamine to glutamate, with cetuximab, an EGFR-targeted monoclonal antibody in preclinical models of CRC. 2D and 3D in vitro assays were executed following treatment with either single agent or combination therapy. The combination of cetuximab with CB-839 resulted in reduced cell viability and demonstrated synergism in several cell lines. In vivo efficacy experiments were performed in cell-line xenograft models propagated in athymic nude mice. Tumor volumes were measured followed by immunohistochemical (IHC) analysis of proliferation (Ki67), mechanistic target of rapamycin (mTOR) signaling (pS6), and multiple mechanisms of cell death to annotate molecular determinants of response. In vivo, a significant reduction in tumor growth and reduced Ki67 and pS6 IHC staining were observed with combination therapy, which was accompanied by increased apoptosis and/or necrosis. The combination showed efficacy in cetuximab-sensitive as well as resistant models. In conclusion, this therapeutic combination represents a promising new precision medicine approach for patients with refractory metastatic WT RAS CRC.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">32652471</PMID><DateRevised><Year>2020</Year><Month>09</Month><Day>28</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">1936-5233</ISSN><JournalIssue CitedMedium="Print"><Volume>13</Volume><Issue>10</Issue><PubDate><Year>2020</Year><Month>Oct</Month></PubDate></JournalIssue><Title>Translational oncology</Title><ISOAbbreviation>Transl Oncol</ISOAbbreviation></Journal><ArticleTitle>Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer.</ArticleTitle><Pagination><MedlinePgn>100828</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S1936-5233(20)30320-X</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.tranon.2020.100828</ELocationID><Abstract><AbstractText>Improving response to epidermal growth factor receptor (EGFR)-targeted therapies in patients with advanced wild-type (WT) RAS colorectal cancer (CRC) remains an unmet need. In this preclinical work, we evaluated a new therapeutic combination aimed at enhancing efficacy by targeting cancer cell metabolism in concert with EGFR. We hypothesized that combined blockade of glutamine metabolism and EGFR represents a promising treatment approach by targeting both the "fuel" and "signaling" components that these tumors need to survive. To explore this hypothesis, we combined CB-839, an inhibitor of glutaminase 1 (GLS1), the mitochondrial enzyme responsible for catalyzing conversion of glutamine to glutamate, with cetuximab, an EGFR-targeted monoclonal antibody in preclinical models of CRC. 2D and 3D in vitro assays were executed following treatment with either single agent or combination therapy. The combination of cetuximab with CB-839 resulted in reduced cell viability and demonstrated synergism in several cell lines. In vivo efficacy experiments were performed in cell-line xenograft models propagated in athymic nude mice. Tumor volumes were measured followed by immunohistochemical (IHC) analysis of proliferation (Ki67), mechanistic target of rapamycin (mTOR) signaling (pS6), and multiple mechanisms of cell death to annotate molecular determinants of response. In vivo, a significant reduction in tumor growth and reduced Ki67 and pS6 IHC staining were observed with combination therapy, which was accompanied by increased apoptosis and/or necrosis. The combination showed efficacy in cetuximab-sensitive as well as resistant models. In conclusion, this therapeutic combination represents a promising new precision medicine approach for patients with refractory metastatic WT RAS CRC.</AbstractText><CopyrightInformation>Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Cohen</LastName><ForeName>Allison S</ForeName><Initials>AS</Initials><AffiliationInfo><Affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Geng</LastName><ForeName>Ling</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhao</LastName><ForeName>Ping</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fu</LastName><ForeName>Allie</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schulte</LastName><ForeName>Michael L</ForeName><Initials>ML</Initials><AffiliationInfo><Affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Graves-Deal</LastName><ForeName>Ramona</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Washington</LastName><ForeName>M Kay</ForeName><Initials>MK</Initials><AffiliationInfo><Affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, C-3322, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Berlin</LastName><ForeName>Jordan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Coffey</LastName><ForeName>Robert J</ForeName><Initials>RJ</Initials><AffiliationInfo><Affiliation>Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, U3218 MRB III, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States; Veterans Health Administration, Tennessee Valley Healthcare System, 1310 24th Avenue South, Nashville, TN 37212, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Manning</LastName><ForeName>H Charles</ForeName><Initials>HC</Initials><AffiliationInfo><Affiliation>Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, 1161 21(st) Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, R0102, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Medical Center North, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, United States. Electronic address: henry.c.manning@vumc.org.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>07</Month><Day>08</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Transl Oncol</MedlineTA><NlmUniqueID>101472619</NlmUniqueID><ISSNLinking>1936-5233</ISSNLinking></MedlineJournalInfo><CoiStatement>Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>06</Month><Day>11</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>06</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>7</Month><Day>12</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>7</Month><Day>12</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>7</Month><Day>12</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32652471</ArticleId><ArticleId IdType="pii">S1936-5233(20)30320-X</ArticleId><ArticleId IdType="doi">10.1016/j.tranon.2020.100828</ArticleId><ArticleId IdType="pmc">PMC7348062</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>États-Unis</li></country><region><li>Tennessee</li></region></list><tree><country name="États-Unis"><region name="Tennessee"><name sortKey="Cohen, Allison S" sort="Cohen, Allison S" uniqKey="Cohen A" first="Allison S" last="Cohen">Allison S. Cohen</name></region><name sortKey="Berlin, Jordan" sort="Berlin, Jordan" uniqKey="Berlin J" first="Jordan" last="Berlin">Jordan Berlin</name><name sortKey="Coffey, Robert J" sort="Coffey, Robert J" uniqKey="Coffey R" first="Robert J" last="Coffey">Robert J. Coffey</name><name sortKey="Fu, Allie" sort="Fu, Allie" uniqKey="Fu A" first="Allie" last="Fu">Allie Fu</name><name sortKey="Geng, Ling" sort="Geng, Ling" uniqKey="Geng L" first="Ling" last="Geng">Ling Geng</name><name sortKey="Graves Deal, Ramona" sort="Graves Deal, Ramona" uniqKey="Graves Deal R" first="Ramona" last="Graves-Deal">Ramona Graves-Deal</name><name sortKey="Manning, H Charles" sort="Manning, H Charles" uniqKey="Manning H" first="H Charles" last="Manning">H Charles Manning</name><name sortKey="Schulte, Michael L" sort="Schulte, Michael L" uniqKey="Schulte M" first="Michael L" last="Schulte">Michael L. Schulte</name><name sortKey="Washington, M Kay" sort="Washington, M Kay" uniqKey="Washington M" first="M Kay" last="Washington">M Kay Washington</name><name sortKey="Zhao, Ping" sort="Zhao, Ping" uniqKey="Zhao P" first="Ping" last="Zhao">Ping Zhao</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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