Simultaneous targeting of PI3K? and a PI3K?-dependent MEK1/2-Erk1/2 pathway for therapy in pediatric B-cell acute lymphoblastic leukemia.

ABSTRACT: B cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy diagnosed in children, and blockade of the abnormally activated PI3K? displayed promising outcomes in B cell acute or chronic leukemias, but the mechanisms are not well understood. Here we report a novel PI3K? selective inhibitor X-370, which displays distinct binding mode with p110? and blocks constitutively active or stimulus-induced PI3K? signaling. X-370 significantly inhibited survival of human B cell leukemia cells in vitro, with associated induction of G1 phase arrest and apoptosis. X-370 abrogated both Akt and Erk1/2 signaling via blockade of PDK1 binding to and/or phosphorylation of MEK1/2. Forced expression of a constitutively active MEK1 attenuated the antiproliferative activity of X-370. X-370 preferentially inhibited the survival of primary pediatric B-ALL cells displaying PI3K?-dependent Erk1/2 phosphorylation, while combined inhibition of PI3K? and MEK1/2 displayed enhanced activity. We conclude that PI3K? inhibition led to abrogation of both Akt and Erk1/2 signaling via a novel PI3K-PDK1/MEK1/2-Erk1/2 signaling cascade, which contributed to its efficacy against B-ALL. These findings support the rationale for clinical testing of PI3K? inhibitors in pediatric B-ALL and provide insights needed to optimize the therapeutic strategy.

SUBMITTER: Wang X 

PROVIDER: S-EPMC4279406 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature