Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts.
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.
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.|The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.
Elena
E
Andreucci
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.|The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.|Current address: Department of Clinical Research, Radiation Oncology Laboratory, University of Bern, Bern, Switzerland.
Paola
P
Francica
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.|Current address: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, United Kingdom.
Antony
A
Fearns
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.
Lesley-Ann
LA
Martin
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.|Tuscany Tumor Institute (ITT) and Excellence Centre for Research, Transfer and High Education DenoTHE, Florence, Italy.
Paola
P
Chiarugi
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.
Clare M
CM
Isacke
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Andrea
A
Morandi
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002224:Carbanilides / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D000077289:Letrozole; D061986:MCF-7 Cells; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009570:Nitriles / Q000494:pharmacology*; D010052:Ovariectomy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013997:Time Factors; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D010671:Phenylurea Compounds; D011743:Pyrimidines
D001141:Aromatase; D047072:Aromatase Inhibitors; D002224:Carbanilides; D000077289:Letrozole; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret; D011960:Receptors, Estrogen; D014230:Triazoles; C522130:NVP-AST487; D010671:Phenylurea Compounds; D011743:Pyrimidines; C561410:CYP19A1 protein, human; C099282:RET protein, human
GDNF; RET; aromatase inhibitors; endocrine therapy; resistance