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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 10
[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
Total Affiliations: 5
Document type: Journal article
Source: ONCOTARGET; v. 6, n. 15, p. 13105-13118, MAY 30 2015.
Web of Science Citations: 14

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)

FAPESP's process: 08/10034-1 - Bone marrow microenvironment and PI3K pathway in resistance to chemotherapy of pediatric acute lymphoblastic leukemia
Grantee:José Andrés Yunes
Support type: Regular Research Grants