惡性膠質(zhì)瘤是最常見的原發(fā)性腦腫瘤,。雖然磷酸肌醇3-激酶（PI3K）信號(hào)在腦膠質(zhì)瘤中非常重要,，其抑制劑能一般性地阻止癌細(xì)胞擴(kuò)散,，但不能誘導(dǎo)細(xì)胞凋亡。
近來脂質(zhì)和蛋白激酶的抑制劑的開發(fā)旨在誘導(dǎo)腫瘤細(xì)胞凋亡,，但早期臨床試驗(yàn)均以失敗而告終,，因?yàn)檫@些抑制劑作用點(diǎn)廣泛，整體毒性也較大,，這表明PI3K抑制劑的聯(lián)合使用具有選擇性合成致死性,。
近日PNAS雜志上刊出的一則研究運(yùn)用臨床蛋白激酶抑制劑,，表明細(xì)胞周期蛋白依賴性激酶（CDK）1/2的臨床抑制劑Roscovitine與PI3K抑制劑PIK-9090能聯(lián)合阻斷抗凋亡蛋白Survivin表達(dá)，促進(jìn)癌細(xì)胞死亡,。
此外,，CDKs過表達(dá)能部分阻斷PIK-75激酶引起的細(xì)胞凋亡。細(xì)胞周期依賴性蛋白激酶(CDK)抑制劑(Roscovitine)和PIK-90結(jié)合,，在人神經(jīng)母細(xì)胞瘤裸鼠體內(nèi)的耐受性良好,，并以合成致死的方式發(fā)揮作用誘導(dǎo)細(xì)胞凋亡。
研究還測(cè)試了臨床Akt和CDK抑制劑,，證明也能在體外能誘導(dǎo)細(xì)胞凋亡,，這項(xiàng)新研究為聯(lián)合治療患者提供了臨床前的依據(jù)。（生物谷：Bioon.com）
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.
