Development of Mek inhibition (MEK-I)-Based Therapeutic Strategies in Acute Myeloid Leukemia (AML) (original) (raw)

Blood, 2008

Abstract

In hematologic malignancies, constitutive activation of the Raf/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Indeed, we have recently demonstrated that selective MEK-I potently inhibit the growth of AML cell lines and ex vivo-cultured primary AML blasts (Blood2006, 108:254). However, these effects are mostly related to the inhibition of cell cycle progression, while apoptosis induction requires higher concentrations of the inhibitors and longer times of exposure. Thus, we investigated MEK-I-induced changes in phospho-protein expression and gene expression profiles, in order to identify relevant downstream targets and to design rational MEK-I-based combination strategies. Analysis of phosphorylation levels of 18 different target proteins performed in OCI-AML3 cells indicated that MEK blockade induces, among other effects, an over-activation of RAF and MEK, suggesting the interruption of a negative f...

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