Litvin Oren, Schwartz Sarit, Wan Zhenmao, Schild Tanya, Rocco Mark, Oh Nul Loren, Chen Bo-Juen, Goddard Noel, Pratilas Christine, Pe'er Dana
Department of Biological Sciences and Department of Systems Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Mol Cell. 2015 Mar 5;57(5):784-796. doi: 10.1016/j.molcel.2014.12.030. Epub 2015 Feb 12.
Drugs that inhibit the MAPK pathway have therapeutic benefit in melanoma, but responses vary between patients, for reasons that are still largely unknown. Here we aim at explaining this variability using pre- and post-MEK inhibition transcriptional profiles in a panel of melanoma cell lines. We found that most targets are context specific, under the influence of the pathway in only a subset of cell lines. We developed a computational method to identify context-specific targets, and found differences in the activity levels of the interferon pathway, driven by a deletion of the interferon locus. We also discovered that IFNα/β treatment strongly enhances the cytotoxic effect of MEK inhibition, but only in cell lines with low activity of interferon pathway. Taken together, our results suggest that the interferon pathway plays an important role in, and predicts, the response to MAPK inhibition in melanoma. Our analysis demonstrates the value of system-wide perturbation data in predicting drug response.
抑制丝裂原活化蛋白激酶（MAPK）途径的药物对黑色素瘤具有治疗益处，但不同患者的反应各不相同，其原因在很大程度上仍不清楚。在这里，我们旨在利用一组黑色素瘤细胞系中MEK抑制前后的转录谱来解释这种变异性。我们发现，大多数靶点具有细胞系特异性，仅在一部分细胞系中受该途径影响。我们开发了一种计算方法来识别细胞系特异性靶点，并发现由于干扰素基因座的缺失，干扰素途径的活性水平存在差异。我们还发现，IFNα/β治疗强烈增强了MEK抑制的细胞毒性作用，但仅在干扰素途径活性较低的细胞系中如此。综上所述，我们的结果表明，干扰素途径在黑色素瘤对MAPK抑制的反应中起重要作用，并可预测该反应。我们的分析证明了全系统扰动数据在预测药物反应方面的价值。
