dc.contributor.author | Andreucci, E | |
dc.contributor.author | Francica, P | |
dc.contributor.author | Fearns, A | |
dc.contributor.author | Martin, L-A | |
dc.contributor.author | Chiarugi, P | |
dc.contributor.author | Isacke, CM | |
dc.contributor.author | Morandi, A | |
dc.date.accessioned | 2016-09-02T10:45:43Z | |
dc.date.issued | 2016-12-06 | |
dc.identifier.citation | Oncotarget, 2016, 7 (49), pp. 80543 - 80553 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/88 | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.doi | 10.18632/oncotarget.11826 | |
dc.description.abstract | The 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. | |
dc.format | Print | |
dc.format.extent | 80543 - 80553 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | IMPACT JOURNALS LLC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Spheroids, Cellular | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice, Nude | |
dc.subject | Breast Neoplasms | |
dc.subject | Neoplasm Invasiveness | |
dc.subject | Carbanilides | |
dc.subject | Nitriles | |
dc.subject | Triazoles | |
dc.subject | Aromatase | |
dc.subject | Receptors, Estrogen | |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | |
dc.subject | Aromatase Inhibitors | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Ovariectomy | |
dc.subject | Tumor Burden | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Transfection | |
dc.subject | Signal Transduction | |
dc.subject | Cell Proliferation | |
dc.subject | Cell Movement | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Time Factors | |
dc.subject | Female | |
dc.subject | Proto-Oncogene Proteins c-ret | |
dc.subject | Molecular Targeted Therapy | |
dc.subject | MCF-7 Cells | |
dc.subject | Letrozole | |
dc.title | Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-08-24 | |
rioxxterms.versionofrecord | 10.18632/oncotarget.11826 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncotarget | |
pubs.issue | 49 | |
pubs.notes | Not known | |
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.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
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.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
pubs.publication-status | Published | |
pubs.volume | 7 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Molecular Cell Biology | |
icr.researchteam | Endocrinology | |
dc.contributor.icrauthor | Martin, Lesley-Ann | |
dc.contributor.icrauthor | Isacke, Clare | |