PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia
André Bortolini Silveira, Angelo Brunelli Albertoni Laranjeira, Gisele Olinto Libanio Rodrigues, Paulo César Leal, Bruno António Cardoso, João Taborda Barata, Rosendo Augusto Yunes, Nilson Ivo Tonin Zanchin, Sílvia Regina Brandalise, José Andrés Yunes
ARTIGO
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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...
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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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CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ
FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP
08/10034–1
Fechado
DOI: https://doi.org/10.18632/oncotarget.3524
Texto completo: https://www.oncotarget.com/article/3524/
PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia
André Bortolini Silveira, Angelo Brunelli Albertoni Laranjeira, Gisele Olinto Libanio Rodrigues, Paulo César Leal, Bruno António Cardoso, João Taborda Barata, Rosendo Augusto Yunes, Nilson Ivo Tonin Zanchin, Sílvia Regina Brandalise, José Andrés Yunes
PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia
André Bortolini Silveira, Angelo Brunelli Albertoni Laranjeira, Gisele Olinto Libanio Rodrigues, Paulo César Leal, Bruno António Cardoso, João Taborda Barata, Rosendo Augusto Yunes, Nilson Ivo Tonin Zanchin, Sílvia Regina Brandalise, José Andrés Yunes
Fontes
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Oncotarget Vol. 6, no. 15 (Apr., 2015), p. 13105-13118 |