Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts.
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Date
2016-12-06Author
Andreucci, E
Francica, P
Fearns, A
Martin, L-A
Chiarugi, P
Isacke, CM
Morandi, A
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Spheroids, Cellular
Animals
Humans
Mice, Nude
Breast Neoplasms
Neoplasm Invasiveness
Carbanilides
Nitriles
Triazoles
Aromatase
Receptors, Estrogen
Antineoplastic Combined Chemotherapy Protocols
Aromatase Inhibitors
Protein Kinase Inhibitors
Ovariectomy
Tumor Burden
Xenograft Model Antitumor Assays
Transfection
Signal Transduction
Cell Proliferation
Cell Movement
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Time Factors
Female
Proto-Oncogene Proteins c-ret
Molecular Targeted Therapy
MCF-7 Cells
Letrozole
Research team
Molecular Cell Biology
Endocrinology
Language
eng
Date accepted
2016-08-24
License start date
2016-12
Citation
Oncotarget, 2016, 7 (49), pp. 80543 - 80553
Publisher
IMPACT JOURNALS LLC