PNAS：双重抑制剂诱导恶性胶质瘤细胞死亡

恶性胶质瘤是最常见的原发性脑肿瘤。虽然磷酸肌醇3-激酶（PI3K）信号在脑胶质瘤中非常重要，其抑制剂能一般性地阻止癌细胞扩散，但不能诱导细胞凋亡。

近来脂质和蛋白激酶的抑制剂的开发旨在诱导肿瘤细胞凋亡，但早期临床试验均以失败而告终，因为这些抑制剂作用点广泛，整体毒性也较大，这表明PI3K抑制剂的联合使用具有选择性合成致死性。

近日PNAS杂志上刊出的一则研究运用临床蛋白激酶抑制剂，表明细胞周期蛋白依赖性激酶（CDK）1/2的临床抑制剂Roscovitine与PI3K抑制剂PIK-9090能联合阻断抗凋亡蛋白Survivin表达，促进癌细胞死亡。

此外，CDKs过表达能部分阻断PIK-75激酶引起的细胞凋亡。细胞周期依赖性蛋白激酶(CDK)抑制剂(Roscovitine)和PIK-90结合，在人神经母细胞瘤裸鼠体内的耐受性良好，并以合成致死的方式发挥作用诱导细胞凋亡。

研究还测试了临床Akt和CDK抑制剂，证明也能在体外能诱导细胞凋亡，这项新研究为联合治疗患者提供了临床前的依据。

doi:10.1073/pnas.1202492109
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Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma

Christine K. Cheng, W. Clay Gustafsonb,et al.

Malignant glioma, the most common primary brain tumor, is generally incurable. Although phosphatidylinositol-3-kinase (PI3K) signaling features prominently in glioma, inhibitors generally block proliferation rather than induce apoptosis. Starting with an inhibitor of both lipid and protein kinases that induced prominent apoptosis and that failed early clinical development because of its broad target profile and overall toxicity, we identified protein kinase targets, the blockade of which showed selective synthetic lethality when combined with PI3K inhibitors. Prioritizing protein kinase targets for which there are clinical inhibitors, we demonstrate that cyclin-dependent kinase (CDK)1/2 inhibitors, siRNAs against CDK1/2, and the clinical CDK1/2 inhibitor roscovitine all cooperated with the PI3K inhibitor PIK-90, blocking the antiapoptotic protein Survivin and driving cell death. In addition, overexpression of CDKs partially blocked some of the apoptosis caused by PIK-75. Roscovitine and PIK-90, in combination, were well tolerated in vivo and acted in a synthetic-lethal manner to induce apoptosis in human glioblastoma xenografts. We also tested clinical Akt and CDK inhibitors, demonstrating induction of apoptosis in vitro and providing a preclinical rationale to test this combination therapy in patients.