Oncotarget

Research Papers:

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

Elena Andreucci, Paola Francica, Antony Fearns, Lesley-Ann Martin, Paola Chiarugi, Clare M. Isacke _ and Andrea Morandi

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Oncotarget. 2016; 7:80543-80553. https://doi.org/10.18632/oncotarget.11826

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Abstract

Elena Andreucci1,2,*, Paola Francica1,2,4,*, Antony Fearns2,5, Lesley-Ann Martin2, Paola Chiarugi1,3, Clare M. Isacke2, Andrea Morandi1

1Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

2The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom

3Tuscany Tumor Institute (ITT) and Excellence Centre for Research, Transfer and High Education DenoTHE, Florence, Italy

4Current address: Department of Clinical Research, Radiation Oncology Laboratory, University of Bern, Bern, Switzerland

5Current address: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, United Kingdom

*Equal first author contribution

Correspondence to:

Clare M. Isacke, email: [email protected]

Andrea Morandi, email: [email protected]

Keywords: RET, GDNF, endocrine therapy, aromatase inhibitors, resistance

Received: March 15, 2016     Accepted: August 24, 2016     Published: September 02, 2016

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.


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