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1 Department of Clinical Medicine, Prevention and Biotechnology, University of Milan-Bicocca, Monza, Italy
2 Department of Oncology, McGill University, Montreal, Canada
3 Laboratoire de Chimie Therapeutique, School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
4 MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom
5 Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy
(Requests for offprints should be addressed to L Mologni at Department of Clinical Medicine and Prevention, DIMEP, University of Milan-Bicocca, via Cadore 48, 20052 Monza, Italy; Email: luca.mologni{at}unimib.it)
Thyroid neoplasia is frequently associated with rearranged during transfection (RET) proto-oncogene mutations that cause hyperactivation of RET kinase activity. Selective inhibition of RET-mediated signaling should lead to an efficacious therapy. SU5416 is a potent inhibitor of vascular endothelial cell growth factor receptor, c-Kit, and FLT-3 receptor tyrosine kinases presently used in clinical trials. We found that SU5416 inhibits RET with similar potency, both in cell-free assays and in cells, thus causing proliferation arrest in oncogenic RET-transfected cells and in papillary thyroid carcinoma (PTC) cells expressing the RET/PTC1 oncogene, but not in RET-negative control cells. SU5416 inhibited RET-mediated signaling through the extracellular signal regulated kinase (ERK) and JNK pathways. In addition, we show that a naturally occurring MEN2 mutation at codon 804 confers resistance to SU5416, but not to the related compound SU4984. We provide a possible explanation to these results by using molecular docking. Finally, SU5416 was also assessed against an array of 52 tyrosine and serine/threonine kinases.
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