文章：

一种基因表达特征区分了多发性骨髓瘤中蛋白酶体抑制剂的先天反应和耐药性

A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma

原文发布日期：2017-06-30

DOI: 10.1038/bcj.2017.56

类型: Original Article

开放获取: 是

英文摘要：

Extensive interindividual variation in response to chemotherapy is a major stumbling block in achieving desirable efficacy in the treatment of cancers, including multiple myeloma (MM). In this study, our goal was to develop a gene expression signature that predicts response specific to proteasome inhibitor (PI) treatment in MM. Using a well-characterized panel of human myeloma cell lines (HMCLs) representing the biological and genetic heterogeneity of MM, we created an in vitro chemosensitivity profile in response to treatment with the four PIs bortezomib, carfilzomib, ixazomib and oprozomib as single agents. Gene expression profiling was performed using next-generation high-throughput RNA-sequencing. Applying machine learning-based computational approaches including the supervised ensemble learning methods Random forest and Random survival forest, we identified a 42-gene expression signature that could not only distinguish good and poor PI response in the HMCL panel, but could also be successfully applied to four different clinical data sets on MM patients undergoing PI-based chemotherapy to distinguish between extraordinary (good and poor) outcomes. Our results demonstrate the use of in vitro modeling and machine learning-based approaches to establish predictive biomarkers of response and resistance to drugs that may serve to better direct myeloma patient treatment options.

摘要翻译： 

化疗反应的广泛个体差异是实现癌症（包括多发性骨髓瘤）理想疗效的主要障碍。本研究旨在开发一种基因表达特征，用于预测多发性骨髓瘤对蛋白酶体抑制剂治疗的特异性反应。通过利用代表多发性骨髓瘤生物学和遗传异质性的人骨髓瘤细胞系面板，我们建立了针对四种蛋白酶体抑制剂（硼替佐米、卡非佐米、伊沙佐米和奥普佐米）单药治疗的体外化疗敏感性谱。采用新一代高通量RNA测序技术进行基因表达分析，并应用基于机器学习的计算方法（包括监督集成学习方法随机森林和随机生存森林），我们鉴定出一个42基因表达特征。该特征不仅能在人骨髓瘤细胞系面板中区分蛋白酶体抑制剂治疗的良好与不良反应，还能成功应用于四组接受蛋白酶体抑制剂化疗的多发性骨髓瘤患者临床数据集，以甄别极端（良好与不良）治疗结局。我们的研究结果证明了利用体外建模和机器学习方法建立药物反应及耐药性预测生物标志物的可行性，这可能有助于更好地指导骨髓瘤患者的治疗选择。

原文链接：

A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma