1. ¹Inserm U528, Institut Curie, Paris cedex 05, France
2. ²UMR 599 Inserm, Institut Paoli-Calmettes, Marseille, France

Correspondence: Dr F Moreau-Gachelin, Inserm U528, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France. E-mail: framoreau@curie.fr

Received 7 September 2006; Revised 9 October 2006; Accepted 23 October 2006; Published online 18 December 2006.

Abstract

Activating mutations in the Kit receptor are frequently observed in various malignancies, pointing Kit as a molecule of interest for drug inhibition. When mutated on Asp 816 (corresponding to Asp 814 in the mouse), as preferentially found in human mastocytosis and acute myeloid leukemia, Kit became non-sensitive to imatinib mesylate (Gleevec). Erythroleukemic cells isolated from Spi-1/PU.1 transgenic mice express Kit mutated at codon 814 (Kit^D814Y or Kit^D814V) or codon 818 (Kit^D818Y). Using these cells in vitro, we demonstrate that the tyrosine kinase inhibitor SU5416 (Semaxinib) induces growth arrest and apoptosis independent of the mutation type by inhibiting the functions of Kit, including Kit autophosphorylation and activation of Akt, Erk1/Erk2 and Stat3 downstream signaling pathways. These findings indicate that SU5416 may be a promising tool to kill cancer cells driven by Kit oncogenic mutations that are resistant to treatment with imatinib mesylate.