PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia

// Andre Bortolini Silveira 1 , Angelo Brunelli Albertoni Laranjeira 1 , Gisele Olinto Libanio Rodrigues 1 , Paulo Cesar Leal 2 , Bruno Antonio Cardoso 3 , Joao Taborda Barata 3 , Rosendo Augusto Yunes 2 , Nilson Ivo Tonin Zanchin 4 , Silvia Regina Brandalise 1 , Jose Andres Yunes 1, 5 1 Laboratorio de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil 2 Departamento de Quimica, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil 3 Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal 4 Instituto Carlos Chagas, Fundacao Oswaldo Cruz, Curitiba, PR, Brazil 5 Departamento de Genetica Medica, Faculdade de Ciencias Medicas, UNICAMP, Campinas, SP, Brazil Correspondence to: Jose Andres Yunes, e-mail: andres@boldrini.org.br Keywords: PI3K, AS605240, T-ALL, drug resistance, glucocorticoids Received: December 01, 2014      Accepted: March 09, 2015      Published: April 01, 2015 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.