Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance
Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance
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DOI：
10.1016/j.molonc.2015.02.008
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发表时间：
2015-06-01
影响因子：
6.6
通讯作者：
Moreira, Jose M. A.
中科院分区：
文献类型：
--
作者：
Jensen, Niels F.;Stenvang, Jan;Moreira, Jose M. A.
目前转移性结直肠癌（CRC）的标准治疗方法是基于伊立替康或奥沙利铂两种化疗药物之一的联合方案。然而，耐药性经常限制这些疗法的临床疗效。为了获得与化疗耐药性相关的机制的新见解，并从三种不同的CRC细胞模型出发，我们产生了一组对奥沙利铂或伊立替康具有获得性耐药性的人结直肠癌细胞系。我们对耐药细胞系变异体的耐药性谱和转录组进行了表征，并将我们的结果与相关临床材料生成的数据集进行了匹配，以推导出推定的耐药生物标志物。我们发现，化学耐药细胞系变异体具有独特的伊立替康或奥沙利铂特异性耐药特征，具有非相互交叉耐药。此外，我们可以确定几个新的，以及一些以前描述的耐药相关基因的每个耐药细胞系的变异。每种化疗耐药细胞系变异体都获得了一组独特的变化，这些变化可能代表了化疗耐药的不同功能亚型。此外，考虑到对后续治疗选择的潜在影响，我们还在相关患者队列中对我们的细胞模型中鉴定的每个特定基因的预测价值进行了探索性分析。(C)2015年欧洲生物化学学会联合会。Elsevier B.V.出版，保留所有权利。
Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.