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A gene expression profile indicative of early stage HER2 targeted therapy response

机译：指示早期HER2靶向治疗反应的基因表达谱

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Background Efficacious application of HER2 -targetting agents requires the identification of novel predictive biomarkers. Lapatinib , afatinib and neratinib are tyrosine kinase inhibitors ( TKIs ) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2 -targeting therapies. Results Treatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1 , ERBB3 , FOXO3a and NR3C1 . The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2 -TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change. Conclusions In these HER2 -expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor. Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.
机译：背景技术HER2靶向剂的有效应用需要鉴定新的预测性生物标志物。拉帕替尼，阿法替尼和那拉替尼是HER2和EGFR生长因子受体的酪氨酸激酶抑制剂（TKIs）。用这些药物，曲妥珠单抗，吉非替尼和细胞毒性疗法对一组乳腺癌细胞系进行了治疗，并使用RT-PCR研究了特定基因组的表达模式，作为对HER2靶向疗法早期药物反应的潜在标志。结果用拉帕替尼，阿法替尼和那拉替尼治疗HER2 TKI敏感的SKBR3和BT474细胞系可诱导RB1CC1，ERBB3，FOXO3a和NR3C1表达增加。响应与敏感性程度直接相关。在表达HER2的HER2-TKI不敏感细胞系MDAMB453中，该表达模式从上调切换到下调。 CCND1基因的表达显示出与药物暴露成反比的响应。 neratinib和afatinib治疗后观察到相似的表达模式。暴露于traztuzumab和拉帕替尼加卡培他滨后，这些模式得以保留。相反，吉非替尼，达沙替尼和表柔比星治疗导致完全不同的表达模式变化。结论在这些表达HER2的细胞系模型中，拉帕替尼，那拉替尼，阿法替尼和曲妥珠单抗治疗产生了特征性和特异性基因表达反应，与细胞系对HER2抑制剂的敏感性成比例。因此，这些基因表达水平的诱导变化的表征可为患者肿瘤HER2抑制剂反应的可能程度和特异性提供有价值的，非常早期的预测因子，可能指导这些试剂的更具体使用。

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