Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts.

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.

• Authors: Elena Andreucci, Paola Francica, Antony Fearns, Lesley-Ann Martin, Paola Chiarugi, Clare M Isacke, Andrea Morandi
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 49 Pg. 80543-80553 (Dec 06 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27602955 (Publication Type: Journal Article)

Chemical References

• Aromatase Inhibitors
• Carbanilides
• NVP-AST487
• Nitriles
• Protein Kinase Inhibitors
• Receptors, Estrogen
• Triazoles
• Letrozole
• Aromatase
• CYP19A1 protein, human
• Proto-Oncogene Proteins c-ret
• RET protein, human

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Aromatase (genetics, metabolism)
• Aromatase Inhibitors (pharmacology)
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Carbanilides (pharmacology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Letrozole
• MCF-7 Cells
• Mice, Nude
• Molecular Targeted Therapy
• Neoplasm Invasiveness
• Nitriles (pharmacology)
• Ovariectomy
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-ret (antagonists & inhibitors, metabolism)
• Receptors, Estrogen (metabolism)
• Signal Transduction (drug effects)
• Spheroids, Cellular
• Time Factors
• Transfection
• Triazoles (pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays