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

Autor(es)

Silveira, Andre Bortolini ^[1] ; Albertoni Laranjeira, Angelo Brunelli ^[1] ; Libanio Rodrigues, Gisele Olinto ^[1] ; Leal, Paulo Cesar ^[2] ; Cardoso, Bruno Antonio ^[3] ; Barata, Joao Taborda ^[3] ; Yunes, Rosendo Augusto ^[2] ; Tonin Zanchin, Nilson Ivo ^[4] ; Brandalise, Silvia Regina ^[1] ; Yunes, Jose Andres ^{[1, 5]}

Afiliação do(s) autor(es)

^[1] Ctr Infantil Boldrini, Lab Biol Mol, Campinas, SP - Brazil

^[2] Univ Fed Santa Catarina, Dept Quim, Florianopolis, SC - Brazil

^[3] Univ Lisbon, Inst Med Mol, Fac Med, Lisbon - Portugal

^[4] Fundacao Oswaldo Cruz, Inst Carlos Chagas, Curitiba, PR - Brazil

^[5] Univ Estadual Campinas, Dept Genet Med, Fac Ciencias Med, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ONCOTARGET; v. 6, n. 15, p. 13105-13118, MAY 30 2015.
• Citações Web of Science: 14

Resumo

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. (AU)

• Processo FAPESP: 08/10034-1 - Microambiente da medula óssea e PI3K na resistência a drogas da leucemia linfóide aguda pediátrica
• Beneficiário: José Andrés Yunes
• Modalidade de apoio: Auxílio à Pesquisa - Regular