Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma.
Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma.
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DOI：
10.1158/1078-0432.ccr-13-1675
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发表时间：
2013-11-15
期刊：
影响因子：
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通讯作者：
Maris JM
中科院分区：
文献类型：
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作者：
Rader J;Russell MR;Hart LS;Nakazawa MS;Belcastro LT;Martinez D;Li Y;Carpenter EL;Attiyeh EF;Diskin SJ;Kim S;Parasuraman S;Caponigro G;Schnepp RW;Wood AC;Pawel B;Cole KA;Maris JM
神经母细胞瘤是一种儿童癌症，其发病率和死亡率仍然很高。最近，许多细胞周期蛋白，特别是 Cyclin D/CDK4/CDK6/RB 网络内的细胞周期蛋白，已被证明在神经母细胞瘤中发挥致癌作用，表明它们的治疗开发可能会改善患者的预后。我们使用高度特异性的 CDK4/6 抑制剂 LEE011 评估了双重 CDK4/CDK6 抑制对神经母细胞瘤活力的影响。 LEE011 处理通过在纳摩尔浓度下诱导细胞抑制，显着降低了 17 种人神经母细胞瘤来源细胞系中 12 种的增殖（敏感细胞系中的平均 IC50 = 307 ± 68 nM）。 LEE011 导致细胞周期停滞和细胞衰老，这分别归因于磷酸化 RB 和 FOXM1 的剂量依赖性减少。此外，神经母细胞瘤异种移植物对 LEE011 的反应性转化为体内环境，因为体外 IC50 值与皮下异种移植物生长延迟程度直接相关。虽然我们的数据表明对 LEE011 敏感的神经母细胞瘤更有可能包含 MYCN 的基因组扩增 (p = 0.01)，但鉴定其他临床可及的生物标志物非常重要。总而言之，我们的数据表明 LEE011 在大部分神经母细胞瘤细胞系和异种移植模型中具有活性，并支持这种 CDK4/6 抑制剂作为该疾病患者治疗方法的临床开发。
Neuroblastoma is a pediatric cancer that continues to exact significant morbidity and mortality. Recently, a number of cell cycle proteins, particularly those within the Cyclin D/CDK4/CDK6/RB network, have been shown to exert oncogenic roles in neuroblastoma, suggesting that their therapeutic exploitation might improve patient outcomes. We evaluated the effect of dual CDK4/CDK6 inhibition on neuroblastoma viability using LEE011, a highly specific CDK4/6 inhibitor. Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nM in sensitive lines). LEE011 caused cell cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. While our data indicate that neuroblastomas sensitive to LEE011 were more likely to contain genomic amplification of MYCN (p = 0.01), the identification of additional clinically accessible biomarkers is of high importance. Taken together, our data show that LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease.