Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia.
Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia.
复制标题
DOI：
10.18632/oncotarget.12394
复制
发表时间：
2016-12-20
期刊：
影响因子：
--
通讯作者：
Agarwal A
中科院分区：
文献类型：
--
作者：
Richard NP;Pippa R;Cleary MM;Puri A;Tibbitts D;Mahmood S;Christensen DJ;Jeng S;McWeeney S;Look AT;Chang BH;Tyner JW;Vitek MP;Odero MD;Sears R;Agarwal A
最近的证据表明，通过SET癌蛋白抑制蛋白磷酸酶2A（PP 2A）肿瘤抑制活性有助于各种癌症的发病机制。在这里，我们证明了SET和c-MYC表达在T-ALL细胞系和原代样品中与健康T细胞相比经常升高。用SET拮抗剂OP 449处理T-ALL细胞恢复了PP 2A的活性，并减少了SET与PP 2A催化亚基的相互作用，导致细胞活力和c-MYC表达以剂量依赖性方式降低。由于磷酸酶和激酶之间的紧密平衡是正常细胞和恶性细胞生长所必需的，我们试图鉴定一种与SET拮抗作用协同作用的激酶抑制剂。我们针对靶向三分之二酪氨酸激酶组的66种化合物的小分子抑制剂筛选测试了各种T-ALL细胞系，发现T-ALL细胞与dovitinib（一种口服活性多靶向小分子受体酪氨酸激酶抑制剂）和OP 449的联合治疗协同降低了所有测试的T-ALL细胞系的活力。在NOTCH依赖性和非依赖性T-ALL细胞系中，OP 449和dovitinib联合治疗可降低总c-MYC水平和磷酸化c-MYC水平，并降低ERK 1/2、AKT和p70 S6激酶活性。总体而言，这些结果表明，联合靶向酪氨酸激酶和丝氨酸/苏氨酸磷酸酶的激活可能会提供新的治疗策略，治疗T-ALL。
Recent evidence suggests that inhibition of protein phosphatase 2A (PP2A) tumor suppressor activity via the SET oncoprotein contributes to the pathogenesis of various cancers. Here we demonstrate that both SET and c-MYC expression are frequently elevated in T-ALL cell lines and primary samples compared to healthy T cells. Treatment of T-ALL cells with the SET antagonist OP449 restored the activity of PP2A and reduced SET interaction with the PP2A catalytic subunit, resulting in a decrease in cell viability and c-MYC expression in a dose-dependent manner. Since a tight balance between phosphatases and kinases is required for the growth of both normal and malignant cells, we sought to identify a kinase inhibitor that would synergize with SET antagonism. We tested various T-ALL cell lines against a small-molecule inhibitor screen of 66 compounds targeting two-thirds of the tyrosine kinome and found that combined treatment of T-ALL cells with dovitinib, an orally active multi-targeted small-molecule receptor tyrosine kinase inhibitor, and OP449 synergistically reduced the viability of all tested T-ALL cell lines. Mechanistically, combined treatment with OP449 and dovitinib decreased total and phospho c-MYC levels and reduced ERK1/2, AKT, and p70S6 kinase activity in both NOTCH-dependent and independent T-ALL cell lines. Overall, these results suggest that combined targeting of tyrosine kinases and activation of serine/threonine phosphatases may offer novel therapeutic strategies for the treatment of T-ALL.