Differential transcriptional effects of EGFR inhibitors.
Differential transcriptional effects of EGFR inhibitors.
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DOI：
10.1371/journal.pone.0102466
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Blumenberg M
中科院分区：
文献类型：
--
作者：
Blumenberg M
EGF及其受体EGFR是细胞、分子和肿瘤生物学中信号转导的范例。EGFR抑制剂是靶向细胞内激酶活性的药物和靶向细胞外配体结合的抗体，用于治疗乳腺癌、肺癌、结肠癌等癌症。名义上影响相同的靶点，抑制剂有不同的效果，这表明抑制剂联合使用可能对癌症治疗有益。为了探索EGFR抑制剂的特异性和共同转录效应，我们对包含346个微阵列的20个个体研究进行了荟萃分析。我们确定了由激酶抑制剂调节的特定基因亚群，那些由抗体调节的基因亚群，以及通过miR-7抑制EGFR表达的基因亚群。以前没有报道过，这些抑制剂显著地诱导溶酶体成分。所有的抑制剂都依赖于相关的转录因子和蛋白激酶，来诱导和抑制转录。然而，我们发现吉非替尼抑制凋亡抑制剂，同时诱导细胞周期抑制剂；相反，厄洛替尼抑制细胞周期和细胞迁移基因，诱导促凋亡基因。egfr靶向抗体特异性抑制细胞运动、发育和分化过程，同时诱导收缩器官。独特的是，miR-7在诱导转录机制的同时抑制细胞周期基因。这些荟萃分析结果表明，不同的抑制剂在靶细胞中具有重叠但截然不同的作用。合理使用egfr靶向组合，即同时使用抗体和多种激酶抑制剂，可能提供更有效的癌症治疗，副作用更少，避免耐药性的产生。此外，我们期望，特定的药物组合治疗可以微调，以达到特定的，个性化的结果。
EGF and its receptor EGFR serve as a paradigm for signaling in cell, molecular and tumor biology. EGFR inhibitors, drugs targeting the intracellular kinase activity and antibodies targeting the extracellular ligand binding, are used to treat breast, lung, colon and other cancers. Nominally affecting the same target, inhibitors have different effects, suggesting that use of inhibitor combinations may provide beneficial in cancer treatment. To explore the specific and the common transcriptional effects of EGFR inhibitors, we present metaanalysis of 20 individual studies comprising 346 microarrays. We identified specific gene subsets regulated by kinase inhibitors, those regulated using antibodies and by suppressing EGFR expression using miR-7. Unreported before, the inhibitors prominently induce lysosome components. All inhibitors rely on related sets of transcription factors and protein kinases, both for transcriptional induction and suppression. However, we find that Gefitinib suppresses apoptosis inhibitors, while inducing cell-cycle inhibitors; conversely, Erlotinib suppresses cell-cycle and cell migration genes, while inducing proapoptotic genes. EGFR-targeting antibodies specifically suppress cell motility, developmental and differentiation processes, while inducing the contractile apparatus. miR-7, distinctively, suppresses cell-cycle genes, while inducing transcription machinery. These metaanalysis results suggest that different inhibitors have overlapping but quite distinct effects in target cells. Judicial use of EGFR-targeting combinations, i.e., simultaneous use of antibodies and multiple kinase inhibitors, may provide more effective cancer treatments with fewer side-effects and avoid development of resistance. We expect, moreover, that specific drug combination treatments can be fine-tuned to achieve specific, personalized results.
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影响因子：
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作者：
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