Silveira André Bortolini, Laranjeira Angelo Brunelli Albertoni, Rodrigues Gisele Olinto Libanio, Leal Paulo César, Cardoso Bruno António, Barata João Taborda, Yunes Rosendo Augusto, Zanchin Nilson Ivo Tonin, Brandalise Sílvia Regina, Yunes José Andrés
Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Oncotarget. 2015 May 30;6(15):13105-18. doi: 10.18632/oncotarget.3524.
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.
PI3K通路在原发性T细胞急性淋巴细胞白血病（T-ALL）细胞中常被过度激活。PI3K通路的激活被认为是T-ALL中糖皮质激素耐药的一种机制，而携带PI3K负调节因子PTEN突变的患者诱导失败和复发风险可能增加。通过对用PI3K抑制剂AS605240处理的T-ALL细胞进行基因表达微阵列分析，我们确定Myc是PI3K通路的一个重要下游靶点。在T-ALL中，发现AS605240基因表达特征与糖皮质激素耐药和复发的基因表达特征之间存在显著关联。AS605240在体外和T-ALL的NOD/SCID异种移植模型中均显示出抗白血病活性，并与糖皮质激素有强烈协同作用。相比之下，PI3K抑制与甲氨蝶呤和柔红霉素表现出拮抗作用，这两种药物优先靶向分裂细胞。然而，通过使用正确的给药方案可以规避这种拮抗相互作用。我们的数据表明了在T-ALL治疗中加入PI3K抑制剂的潜在益处和困难。
