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

Andreucci, Elena; Francica, Paola; Fearns, Antony; Martin, Lesley-Ann; Chiarugi, Paola; Isacke, Clare M; Morandi, Andrea (2016). Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts. OncoTarget, 7(49), pp. 80543-80553. Impact Journals LLC 10.18632/oncotarget.11826

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology

UniBE Contributor:

Francica, Paola

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1949-2553

Publisher:

Impact Journals LLC

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

16 Mar 2017 10:21

Last Modified:

11 Sep 2017 21:26

Publisher DOI:

10.18632/oncotarget.11826

PubMed ID:

27602955

Uncontrolled Keywords:

GDNF; RET; aromatase inhibitors; endocrine therapy; resistance

BORIS DOI:

10.7892/boris.92705

URI:

https://boris.unibe.ch/id/eprint/92705

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