An inhibitor of cyclin-dependent kinases suppresses TLR signaling and increases the susceptibility of cancer patients to herpes viridae
An inhibitor of cyclin-dependent kinases suppresses TLR signaling and increases the susceptibility of cancer patients to herpes viridae
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DOI：
10.4161/cc.10.1.14445
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发表时间：
2011-01
期刊：
影响因子：
4.3
通讯作者：
Mustapha Zoubir;C. Flament;Abdelaziz Gdoura;R. Bahleda;Elena Litvinova;V. Soumelis;R. Conforti;S. Viaud;J. Soria;G. Kroemer;L. Zitvogel;N. Chaput
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文献类型：
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作者：
Mustapha Zoubir;C. Flament;Abdelaziz Gdoura;R. Bahleda;Elena Litvinova;V. Soumelis;R. Conforti;S. Viaud;J. Soria;G. Kroemer;L. Zitvogel;N. Chaput
细胞周期蛋白依赖性激酶（CDK）抑制剂因其恢复细胞周期控制的潜在能力而被认为是癌症治疗的优秀候选药物。第一代 CDK 抑制剂表现出一定的临床优势，这可能是由于脱靶效应阻止它们达到治疗浓度。使用第二代多 CDK 抑制剂 PHA-793887 对欧洲两个地点的总共 19 名晚期难治性恶性肿瘤患者进行了一项 I 期剂量递增研究：英国利兹的利兹大学和圣詹姆斯肿瘤研究所以及法国维勒伊夫的古斯塔夫·鲁西研究所 (IGR)。 15 名患者在 IGR 接受治疗。其中六名患者表现出疱疹病毒复制的重新激活。体外实验表明，PHA-793887 严重损害树突状细胞 (DC) 中 Toll 样受体（如 TLR3、TLR4 和 TLR9）的信号传导，从而抑制成熟 DC 产生多种细胞因子（1 型干扰素、白介素-6、-10、-12 和肿瘤坏死因子-α），以及自然杀伤细胞由 DC 刺激的干扰素-γ 产生。 PHA-793887 的脱靶之一——糖原合成酶-3β (GSK-3β) 的药理抑制不会导致此类免疫缺陷。总而言之，这些数据强调了 PHA-793887 迄今为止未被怀疑的免疫抑制作用。
Cyclin-dependent kinase (CDK) inhibitors have been considered as excellent drug candidates for cancer therapy owing to their potential capacity to restore cell cycle control. The first generation of CDK inhibitors showed modest clinical advantages that could be attributed to off-target effects preventing them from reaching therapeutic concentrations. A phase I dose-escalation study using the second generation multi-CDK inhibitor PHA-793887 was conducted on a total of 19 patients with advanced refractory malignancies in two sites in Europe: the University of Leeds and St. James’s Institute of Oncology, Leeds, UK, and the Institut Gustave Roussy, Villeujf, France (IGR). Fifteen patients were treated at IGR. Six among these patients manifested the reactivation of herpes virus replication. In vitro experiments revealed that PHA-793887 severely impaired signaling by toll-like receptors (such as TLR3, TLR4 and TLR9) in dendritic cells (DC), thus suppressing the production of multiple cytokines (type 1 interferon, interleukin-6,-10, -12, and tumor necrosis factor- α) by mature DC, as well as the DC-stimulated production of interferon-γ by natural killer cells. Pharmacological inhibition of glycogen synthase-3β (GSK-3β), one of the off-targets of PHA-793887, did not cause such immunological defects. Altogether, these data underscore a hitherto unsuspected immunosuppressive effect of PHA-793887.