A sequential blockade strategy for the design of combination therapies to overcome oncogene addiction in chronic myelogenous leukemia
A sequential blockade strategy for the design of combination therapies to overcome oncogene addiction in chronic myelogenous leukemia
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DOI：
10.1158/0008-5472.can-06-1216
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发表时间：
2006-11-15
期刊：
影响因子：
11.2
通讯作者：
Plunkett, William
中科院分区：
文献类型：
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作者：
Chen, Rong;Gandhi, Varsha;Plunkett, William
一些肿瘤依赖于单个癌基因的持续活性来维持其恶性表型。研究得最好的例子是慢性粒细胞白血病（CML）中的Bcr-Ab 1融合蛋白。尽管Ab 1激酶抑制剂伊马替尼对慢性期CML的临床成功强调了开发针对该目标的治疗策略的重要性，但对伊马替尼的耐药性对该药物的CML治疗的最终成功构成了主要问题。我们假设一个顺序的封锁策略，旨在减少Bcr-Ab 1蛋白的表达，与补充伊马替尼对激酶活性的作用的目标。在这项研究中，flavopiridol，转录抑制剂，高三尖杉酯碱（HHT），蛋白质合成抑制剂，和伊马替尼单独和联合使用对Bcr-Ab 1阳性的人CML细胞系K562。Flavopiridol单独抑制磷酸化的RNA聚合酶II COOH末端结构域，特别是减少RNA聚合酶II指导的mRNA合成，并降低Bcr-Ab 1转录水平。HHT抑制蛋白质合成，降低Bcr-Ab 1蛋白水平。伊马替尼直接抑制Bcr-Ab 1的激酶活性。如通过中效法所评估的，夫拉匹罗和HHT以及夫拉匹罗和伊马替尼的组合协同降低了集落形成。与同时给药相比，HHT和伊马替尼顺序给药时观察到更大的协同作用。转染表达Bcr-Ab 1的E255 K和T315 I突变的伊马替尼耐药Ba/F3细胞对flavopiridol和HHT没有交叉耐药。这些结果为转录和/或翻译抑制剂与特异性激酶抑制剂的组合提供了理论依据。
Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Ab1 fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Ab1 kinase inhibitor imatinib against chronic-phase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Ab1 protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Ab1-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II-directed mRNA synthesis, and decreased the Bcr-Ab1 transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Ab1 protein level. Imatinib directly inhibited the kinase activity of Bcr-Ab1. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Ab1 were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors.