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Les mitochondries nouvelles cibles thérapeutiques potentielles dans le cancer du pancréas -

May 2007 Oncogene

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

Auteurs

Kosmider O, Denis N, Dubreuil P, Moreau-Gachelin F

Résumé

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.

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