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dc.contributor.authorAndreucci, Een_US
dc.contributor.authorFrancica, Pen_US
dc.contributor.authorFearns, Aen_US
dc.contributor.authorMartin, L-Aen_US
dc.contributor.authorChiarugi, Pen_US
dc.contributor.authorIsacke, CMen_US
dc.contributor.authorMorandi, Aen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2016-09-02T10:45:43Z
dc.date.issued2016-12-06en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/27602955en_US
dc.identifier11826en_US
dc.identifier.citationOncotarget, 2016, 7 (49), pp. 80543 - 80553en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/88
dc.identifier.eissn1949-2553en_US
dc.identifier.doi10.18632/oncotarget.11826en_US
dc.description.abstractThe majority of breast cancers are estrogen receptor positive (ER+). Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER+ breast cancers. However, AI resistance remains a major challenge. We have demonstrated previously that increased GDNF/RET signaling in ER+ breast cancers promotes AI resistance. Here we investigated the efficacy of different small molecule RET kinase inhibitors, sunitinib, cabozantinib, NVP-BBT594 and NVP-AST487, and the potential of combining a RET inhibitor with the AI letrozole in ER+ breast cancers. The most effective inhibitor identified, NVP-AST487, suppressed GDNF-stimulated RET downstream signaling and 3D tumor spheroid growth. Ovariectomized mice were inoculated with ER+ aromatase-overexpressing MCF7-AROM1 cells and treated with letrozole, NVP-AST487 or the two drugs in combination. Surprisingly, the three treatment regimens showed similar efficacy in impairing MCF7-AROM1 tumor growth in vivo. However in vitro, NVP-AST487 was superior to letrozole in inhibiting the GDNF-induced motility and tumor spheroid growth of MCF7-AROM1 cells and required in combination with letrozole to inhibit GDNF-induced motility in BT474-AROM3 aromatase expressing cells. These data indicate that inhibiting RET is as effective as the current therapeutic regimen of AI therapy but that a combination treatment may delay cancer cell dissemination and metastasis.en_US
dc.format.extent80543 - 80553en_US
dc.languageengen_US
dc.language.isoengen_US
dc.subjectGDNFen_US
dc.subjectRETen_US
dc.subjectaromatase inhibitorsen_US
dc.subjectendocrine therapyen_US
dc.subjectresistanceen_US
dc.subjectAnimalsen_US
dc.subjectAntineoplastic Combined Chemotherapy Protocolsen_US
dc.subjectAromataseen_US
dc.subjectAromatase Inhibitorsen_US
dc.subjectBreast Neoplasmsen_US
dc.subjectCarbanilidesen_US
dc.subjectCell Movementen_US
dc.subjectCell Proliferationen_US
dc.subjectDose-Response Relationship, Drugen_US
dc.subjectDrug Resistance, Neoplasmen_US
dc.subjectFemaleen_US
dc.subjectHumansen_US
dc.subjectLetrozoleen_US
dc.subjectMCF-7 Cellsen_US
dc.subjectMice, Nudeen_US
dc.subjectMolecular Targeted Therapyen_US
dc.subjectNeoplasm Invasivenessen_US
dc.subjectNitrilesen_US
dc.subjectOvariectomyen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectProto-Oncogene Proteins c-reten_US
dc.subjectReceptors, Estrogenen_US
dc.subjectSignal Transductionen_US
dc.subjectSpheroids, Cellularen_US
dc.subjectTime Factorsen_US
dc.subjectTransfectionen_US
dc.subjectTriazolesen_US
dc.subjectTumor Burdenen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.titleTargeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts.en_US
dc.typeJournal Article
dcterms.dateAccepted2016-08-24en_US
rioxxterms.versionofrecord10.18632/oncotarget.11826en_US
rioxxterms.licenseref.startdate2016-12-06en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfOncotargeten_US
pubs.issue49en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Cell Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.publication-statusPublisheden_US
pubs.volume7en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMolecular Cell Biologyen_US
icr.researchteamEndocrinologyen_US
dc.contributor.icrauthorIsacke, Clareen_US
dc.contributor.icrauthorMartin, Lesley-Annen_US


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