Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts.
Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts.
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DOI：
10.1158/0008-5472.can-09-4559
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Waldman T
中科院分区：
文献类型：
--
作者：
Michaud K;Solomon DA;Oermann E;Kim JS;Zhong WZ;Prados MD;Ozawa T;James CD;Waldman T
细胞周期蛋白依赖性激酶4和6（cdk 4/6）的激活发生在大多数多形性胶质母细胞瘤（GBM）肿瘤，并代表了一个有前途的小分子抑制剂的发展的分子靶点。在本研究中，我们研究了不同GBM细胞系和异种移植物对PD-0332991（一种cdk 4/6特异性抑制剂）的分子决定因素和体内反应。PD-0332991对一组GBM细胞系的体外试验显示，无论其他遗传病变如何，16种Rb活性细胞系中的每一种都具有强效G1细胞周期阻滞和衰老诱导作用，而Rb纯合失活的5种细胞系中的每一种都对治疗完全耐药。Rb表达的shRNA缺失赋予GBM细胞对PD-0332991的抗性，进一步证明Rb对cdk 4/6抑制的敏感性的需要。发现PD-0332991可有效穿过血脑屏障，并被证明可高效抑制颅内GBM异种移植肿瘤的生长，包括替莫唑胺初始治疗后复发的肿瘤。值得注意的是，接受PD-0332991的小鼠在治疗期间没有显著的疾病进展或死亡。此外，PD-0332991和放射治疗的联合治疗与单独治疗相比，生存获益显著增加。总之，我们的结果支持PD-0332991对新诊断以及复发性GBM的临床试验评价，并表明Rb状态是该疗法潜在获益的主要决定因素。
Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6 specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induction of senescence in each of 16 Rb-proficient cell lines regardless of other genetic lesions, whereas each of 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. shRNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 had significant disease progression or died while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly-diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy.