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首页> 外文期刊>Cell cycle >Activities of multiple cancer-related pathways are associated with BRAF mutation and predict the resistance to BRAF/MEK inhibitors in melanoma cells
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Activities of multiple cancer-related pathways are associated with BRAF mutation and predict the resistance to BRAF/MEK inhibitors in melanoma cells

机译：多种癌症相关途径的活动与BRAF突变相关，并预测黑色素瘤细胞对BRAF / MEK抑制剂的耐药性

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Drug resistance is a major obstacle in the targeted therapy of melanoma using BRAF/MEK inhibitors. This study was to identify BRAF V600E-associated oncogenic pathways that predict resistance of BRAF-mutated melanoma to BRAF/MEK inhibitors. We took in silico approaches to analyze the activities of 24 cancer-related pathways in melanoma cells and identify those whose activation was associated with BRAF V600E and used the support vector machine (SVM) algorithm to predict the resistance of BRAF-mutated melanoma cells to BRAF/MEK inhibitors. We then experimentally confirmed the in silico findings. In a microarray gene expression dataset of 63 melanoma cell lines, we found that activation of multiple oncogenic pathways preferentially occurred in BRAF-mutated melanoma cells. This finding was reproduced in 5 additional independent melanoma datasets. Further analysis of 46 melanoma cell lines that harbored BRAF mutation showed that 7 pathways, including TNFα, EGFR, IFNα, hypoxia, IFNγ, STAT3, and MYC, were significantly differently expressed in AZD6244-resistant compared with responsive melanoma cells. A SVM classifier built on this 7-pathway activation pattern correctly predicted the response of 10 BRAF-mutated melanoma cell lines to the MEK inhibitor AZD6244 in our experiments. We experimentally showed that TNFα, EGFR, IFNα, and IFNγ pathway activities were also upregulated in melanoma cell A375 compared with its sub-line DRO, while DRO was much more sensitive to AZD6244 than A375. In conclusion, we have identified specific oncogenic pathways preferentially activated in BRAF-mutated melanoma cells and a pathway pattern that predicts resistance of BRAF-mutated melanoma to BRAF/MEK inhibitors, providing novel clinical implications for melanoma therapy.
机译：耐药性是使用BRAF / MEK抑制剂靶向治疗黑色素瘤的主要障碍。这项研究旨在鉴定BRAF V600E相关的致癌途径，该途径可预测BRAF突变的黑色素瘤对BRAF / MEK抑制剂的耐药性。我们采用计算机模拟方法分析了黑色素瘤细胞中24种与癌症相关的途径的活动，并鉴定了那些与BRAF V600E激活有关的途径，并使用支持向量机（SVM）算法来预测BRAF突变的黑色素瘤细胞对BRAF的耐药性/ MEK抑制剂。然后，我们通过实验确认了计算机模拟的发现。在63个黑色素瘤细胞系的微阵列基因表达数据集中，我们发现多个致癌途径的激活优先发生在BRAF突变的黑色素瘤细胞中。该发现在另外5个独立的黑色素瘤数据集中得到了再现。对具有BRAF突变的46种黑色素瘤细胞系的进一步分析显示，与反应性黑色素瘤细胞相比，包括AZn6244耐药性在内的7种途径（包括TNFα，EGFR，IFNα，低氧，IFNγ，STAT3和MYC）在AZD6244耐药性中表达差异显着。基于此7途径激活模式的SVM分类器在我们的实验中正确预测了10个BRAF突变的黑色素瘤细胞系对MEK抑制剂AZD6244的反应。我们的实验表明，与亚系DRO相比，黑色素瘤细胞A375中的TNFα，EGFR，IFNα和IFNγ途径活性也被上调，而DRO对AZD6244的敏感性比A375高得多。总之，我们已经确定了在BRAF突变的黑色素瘤细胞中优先激活的特定致癌途径，以及预测BRAF突变的黑色素瘤对BRAF / MEK抑制剂耐药的途径模式，为黑色素瘤治疗提供了新的临床意义。

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