Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib
Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib
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DOI：
10.1158/1535-7163.mct-06-0255
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发表时间：
2007-01-01
影响因子：
5.7
通讯作者：
Rettig, Matthew B.
中科院分区：
文献类型：
--
作者：
An, Jiabin;Rettig, Matthew B.
在肾细胞癌（RCC）模型中，蛋白酶体抑制剂硼替佐米的最大细胞毒性依赖于组成型核因子KB（NF-κ B）活性的有效阻断。通过表皮生长因子受体（EGFR）的信号传导已显示导致NF-κ B活化。因此，我们试图研究抑制EGFR是否使RCC细胞对硼替佐米的细胞毒性作用敏感。我们首先确定了组成型NF-κ B活性依赖于RCC细胞中通过EGFR的信号传导。事实上，用EGFR酪氨酸激酶抑制剂（TKI）阻断EGFR信号传导导致NF-κ B活性的抑制。使用药理学和遗传学方法，我们还表明EGFR介导的NF-KB激活通过磷脂酰肌醇-3-OH激酶/AKT途径发生。当用EGFR-TKI预处理RCC细胞时，EGFR-TKI和硼替佐米的组合导致协同细胞毒性作用，但用硼替佐米预处理观察到拮抗相互作用。药物测序对NF-κ B活性抑制作用的评价显示，EGFR-TKI预处理显著增强了硼替佐米的NF-κ B抑制作用，而硼替佐米预暴露导致次优NF-κ B阻断，因此为药物相互作用结果提供了生化解释。我们的结论是，在RCC细胞中观察到的组成型NF-κ B活性介导，至少部分，通过EGFR/磷脂酰肌醇-3-OH激酶/AKT信号级联。EGFR-TKI预处理通过抑制组成型NF-κ B活性对硼替佐米介导的细胞毒性增敏。硼替佐米和目前批准的EGFR抑制剂的组合保证了临床研究。
In renal cell carcinoma (RCC) models, maximal cytotoxicity of the proteasome inhibitor bortezomib is dependent on efficient blockade of constitutive nuclear factor KB (NF-KB) activity. Signaling through the epidermal growth factor receptor (EGFR) has been shown to result in NF-KB activation. Thus, we sought to investigate whether inhibition of the EGFR sensitizes RCC cells to the cytotoxic effects of bortezomib. We first established that constitutive NF-KB activity is dependent on signaling through the EGFR in RCC cells. Indeed, blockade of EGFR signaling with an EGFR tyrosine kinase inhibitor (TKI) resulted in inhibition of NF-KB activity. Using pharmacologic and genetic approaches, we also showed that EGFR-mediated NF-KB activation occurs through the phosphotidylinositol-3-OH kinase/AKT pathway. Combinations of the EGFR-TKI and bortezomib resulted in synergistic cytotoxic effects when RCC cells were pretreated with the EGFR-TKI, but an antagonistic interaction was observed with bortezomib pretreatment. Evaluation of the effects of drug sequencing on inhibition of NF-KB activity revealed that EGFR-TKI pretreatment markedly augmented the NF-KB inhibitory effect of bortezomib, whereas bortezomib preexposure resulted in suboptimal NF-KB blockade and thus provides a biochemical explanation for the drug interaction results. We conclude that the constitutive NF-KB activity observed in RCC cells is mediated, at least in part, through an EGFR/phosphotidylinositol-3-OH kinase/AKT signaling cascade. Pretreatment with an EGFR-TKI sensitizes to bortezomib-mediated cytotoxicity by inhibiting constitutive NF-KB activity. The combination of bortezomib and a currently approved EGFR inhibitor warrants clinical investigation.