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

dc.creatorSilveira, André Bortolini
dc.creatorLaranjeira, Angelo Brunelli Albertoni
dc.creatorRodrigues, Gisele Olinto Libanio
dc.creatorLeal, Paulo César
dc.creatorCardoso, Bruno Antônio
dc.creatorBarata, João Taborda
dc.creatorYunes, Rosendo Augusto
dc.creatorZanchin, Nilson Ivo Tonin
dc.creatorBrandalise, Silva Regina
dc.creatorYunes, José Andrés
dc.date2016-08-30T18:48:45Z
dc.date2016-08-30T18:48:45Z
dc.date2015
dc.date.accessioned2023-09-26T20:56:42Z
dc.date.available2023-09-26T20:56:42Z
dc.identifierSILVEIRA, André Bortolini et al. PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia. Oncotarget, v. 6, n. 15, p. 13105-13118, 2014.
dc.identifier1949-2553
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/15561
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8866590
dc.descriptionThis work was supported by grants from FAPESP (08/10034–1).
dc.descriptionThe 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.
dc.formatapplication/pdf
dc.languagepor
dc.rightsopen access
dc.subjectAS605240
dc.subjectPI3K
dc.subjectT-ALL
dc.subjectdrug resistance
dc.subjectglucocorticoids
dc.subjectResistência a Medicamentos
dc.subjectGlucocorticoides
dc.subjectLeucemia-Linfoma Linfoblástico de Células Precursoras
dc.titlePI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia
dc.typeArticle


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