p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells
p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells
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DOI：
10.1093/neuonc/nos114
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发表时间：
2012-07-01
期刊：
影响因子：
15.9
通讯作者：
Sarkaria, Jann N.
中科院分区：
文献类型：
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作者：
Cen, Ling;Carlson, Brett L.;Sarkaria, Jann N.
p16（INK 4a）-Cdk 4/6-Rb通路的失调在多形性胶质母细胞瘤（GBM）患者中常见，并且是合理的治疗靶点。在此，我们在GBM异种移植物的马约组中表征了p16（INK 4a）-Cdk 4/6-Rb通路，所述异种移植物是从GBM患者的原代组织样本建立的，并评估了它们对PD 0332991（Cdk 4/6的特异性抑制剂）的反应。在本研究中评价的所有GBM异种移植物系都具有p16（INK 4a）-Cdk 4/6-Rb途径的破坏。使用来自选定GBM异种移植系的短期外植体培养物进行的体外评价显示，在CDKN 2A/B-p16缺失（INK 4a）和CDK 4单拷贝缺失（GBM 22）、高水平CDK 6扩增（GBM 34）或CDKN 2C/p18缺失（INK 4c）（GBM 43）的细胞系中，PD 0332991有效地将细胞周期阻滞在G1期，并剂量依赖性地抑制细胞增殖。相反，2个具有p16（INK 4a）表达和CDK 4扩增（GBM 5）或RB突变（GBM 28）的GBM系对PD 0332991完全耐药。筛选了另外的异种移植物系，并鉴定GBM 63具有p16（INK 4a）表达和CDK 4扩增。与GBM 5的结果相似，GBM 63对PD 0332991治疗具有抗性。在原位存活模型中，用PD 0332991处理GBM 6异种移植物（CDKN 2A/B缺失和CDK 4野生型）显著抑制肿瘤细胞增殖并延长存活。总的来说，这些数据支持缺乏p16（INK 4a）表达和具有非扩增CDK 4和野生型RB状态的GBM肿瘤可能对使用PD 0332991的Cdk 4/6抑制更敏感的概念。
Deregulation of the p16(INK4a)-Cdk4/6-Rb pathway is commonly detected in patients with glioblastoma multiforme (GBM) and is a rational therapeutic target. Here, we characterized the p16(INK4a)-Cdk4/6-Rb pathway in the Mayo panel of GBM xenografts, established from primary tissue samples from patients with GBM, and evaluated their response to PD0332991, a specific inhibitor of Cdk4/6. All GBM xenograft lines evaluated in this study had disruptions in the p16(INK4a)-Cdk4/6-Rb pathway. In vitro evaluation using short-term explant cultures from selected GBM xenograft lines showed that PD0332991 effectively arrested cell cycle in G1-phase and inhibited cell proliferation dose-dependently in lines deleted for CDKN2A/B-p16(INK4a) and either single-copy deletion of CDK4 (GBM22), high-level CDK6 amplification (GBM34), or deletion of CDKN2C/p18(INK4c) (GBM43). In contrast, 2 GBM lines with p16(INK4a) expression and either CDK4 amplification (GBM5) or RB mutation (GBM28) were completely resistant to PD0332991. Additional xenograft lines were screened, and GBM63 was identified to have p16(INK4a) expression and CDK4 amplification. Similar to the results with GBM5, GBM63 was resistant to PD0332991 treatment. In an orthotopic survival model, treatment of GBM6 xenografts (CDKN2A/B-deleted and CDK4 wild-type) with PD0332991 significantly suppressed tumor cell proliferation and prolonged survival. Collectively, these data support the concept that GBM tumors lacking p16(INK4a) expression and with nonamplified CDK4 and wild-type RB status may be more susceptible to Cdk4/6 inhibition using PD0332991.