ABCG2 and ABCB1 Limit the Efficacy of Dasatinib in a PDGF-B-Driven Brainstem Glioma Model.
ABCG2 and ABCB1 Limit the Efficacy of Dasatinib in a PDGF-B-Driven Brainstem Glioma Model.
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DOI：
10.1158/1535-7163.mct-15-0093
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发表时间：
2016-05
影响因子：
5.7
通讯作者：
Becher OJ
中科院分区：
文献类型：
--
作者：
Mittapalli RK;Chung AH;Parrish KE;Crabtree D;Halvorson KG;Hu G;Elmquist WF;Becher OJ
达沙替尼是一种多激酶抑制剂，正在进行神经胶质瘤的临床试验，迄今为止未能表现出显着的疗效。我们利用遗传和药理学方法研究了血脑屏障（BBB）中表达的ABC外排转运蛋白ABCG2和ABCB1是否限制达沙替尼治疗神经胶质瘤的疗效。我们使用 abcg2/abcb1 野生型 (ABC WT) 或 abcg2/abcb1 敲除小鼠 (ABC KO)，利用血小板衍生生长因子 B 和 p53 缺失驱动的遗传性脑干胶质瘤小鼠模型。首先，我们观察到 ABC KO 小鼠与 ABC WT 小鼠相比，脑干胶质瘤肿瘤潜伏期显着延长（中位生存期分别为 47 天和 34 天）。达沙替尼治疗使患有脑干胶质瘤的 ABC KO 小鼠的存活率几乎翻倍（44 天与 80 天）。 Elacridar 是一种 ABCG2 和 ABCB1 抑制剂，可显着提高达沙替尼对患有脑干胶质瘤的 ABC WT 小鼠的疗效（42 天与 59 天）。药代动力学分析表明，与 ABC WT 小鼠相比，ABC KO 小鼠中达沙替尼递送至正常大脑而非肿瘤核心的量显着增加。令人惊讶的是，elacridar 并没有显着增加达沙替尼向 ABC WT 小鼠正常大脑或肿瘤核心的递送。接下来，我们通过组织对德克萨斯红葡聚糖的渗透性进行评估，证明该模型的 BBB 紧密连接受到损害。最后，elaridar 增加达沙替尼的细胞毒性，与体外 ABCG2 和 ABCB1 表达无关。总之，elaridar 提高了达沙替尼在脑干胶质瘤模型中的疗效，而没有显着增加其向肿瘤核心的递送。
Dasatinib is a multi-kinase inhibitor in clinical trials for glioma, and thus far failed to demonstrate significant efficacy. We investigated whether the ABC efflux transporters, ABCG2 and ABCB1, expressed in the blood-brain barrier (BBB), are limiting the efficacy of dasatinib in the treatment of glioma using genetic and pharmacological approaches. We utilized a genetic brainstem glioma mouse model driven by platelet-derived growth factor-B and p53 loss using abcg2/abcb1 wild type (ABC WT) or abcg2/abcb1 knockout mice (ABC KO). First, we observed that brainstem glioma tumor latency is significantly prolonged in ABC KO versus ABC WT mice (median survival of 47 vs. 34 days). Dasatinib treatment nearly doubles the survival of brainstem glioma-bearing ABC KO mice (44 vs. 80 days). Elacridar, an ABCG2 and ABCB1 inhibitor, significantly increases the efficacy of dasatinib in brainstem glioma-bearing ABC WT mice (42 vs. 59 days). Pharmacokinetic analysis demonstrates that dasatinib delivery into the normal brain, but not into the tumor core, is significantly increased in ABC KO mice compared to ABC WT mice. Surprisingly, elacridar did not significantly increase dasatinib delivery into the normal brain or the tumor core of ABC WT mice. Next, we demonstrate that the tight junctions of the BBB of this model are compromised as assessed by tissue permeability to Texas Red dextran. Lastly, elacridar increases the cytotoxicity of dasatinib independent of ABCG2 and ABCB1 expression in vitro. In conclusion, elacridar improves the efficacy of dasatinib in a brainstem glioma model without significantly increasing its delivery to the tumor core.