PI3K Inhibition Synergizes with Glucocorticoids but Antagonizes with Methotrexate in T-cell Acute Lymphoblastic Leukemia

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Apr 15

PMID 25869207

Citations 24

Authors

Andre Bortolini Silveira

Angelo Brunelli Albertoni Laranjeira

Gisele Olinto Libanio Rodrigues

Paulo Cesar Leal

Bruno Antonio Cardoso

Joao Taborda Barata

Rosendo Augusto Yunes

Nilson Ivo Tonin Zanchin

Silvia Regina Brandalise

Jose Andres Yunes

Affiliations

Soon will be listed here.

Abstract

The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy.

Citing Articles

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