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Semaxinib (SU5416) as a therapeutic agent targeting oncogenic Kit mutants resistant to imatinib mesylate

Oncogene volume 26, pages 3904–3908 (2007)Cite this article

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 (KitD814Y or KitD814V) or codon 818 (KitD818Y). 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.

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Acknowledgements

We thank C Guillouf and R Monni for many helpful discussions and F Wendling for comments on the manuscript. This work was supported by grants from the Institut National de la Santé Et de la Recherche Médicale, the Institut Curie (Paris), the Association pour la Recherche sur le Cancer, the Fondation de France and the Association Christelle Bouillot.

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Authors and Affiliations

  1. Inserm U528, Institut Curie, Paris cedex 05, France

    O Kosmider, N Denis & F Moreau-Gachelin

  2. UMR 599 Inserm, Institut Paoli-Calmettes, Marseille, France

    P Dubreuil

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  1. O Kosmider
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  2. N Denis
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  3. P Dubreuil
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  4. F Moreau-Gachelin
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Correspondence to F Moreau-Gachelin.

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Kosmider, O., Denis, N., Dubreuil, P. et al. Semaxinib (SU5416) as a therapeutic agent targeting oncogenic Kit mutants resistant to imatinib mesylate. Oncogene 26, 3904–3908 (2007). https://doi.org/10.1038/sj.onc.1210159

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