PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia
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André Bortolini Silveira1, Angelo Brunelli Albertoni Laranjeira1, Gisele Olinto Libanio Rodrigues1, Paulo César Leal2, Bruno António Cardoso3, João Taborda Barata3, Rosendo Augusto Yunes2, Nilson Ivo Tonin Zanchin4, Sílvia Regina Brandalise1, José Andrés Yunes1,5
1Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil
2Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
3Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
4Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, PR, Brazil
5Departamento de Genética Médica, Faculdade de Ciências Médicas, UNICAMP, Campinas, SP, Brazil
José Andrés Yunes, e-mail: firstname.lastname@example.org
Keywords: PI3K, AS605240, T-ALL, drug resistance, glucocorticoids
Received: December 01, 2014 Accepted: March 09, 2015 Published: April 01, 2015
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.
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