基于结直肠癌细胞系MIC50相关基因对的基础耐药评分模型构建

The development of a general drug resistance score model basedon MIC50 related gene pairs in colorectal cancer cell lines

癌细胞系模型已广泛用于药物敏感性测试及耐药标志筛选。然而研究者常忽视癌细胞系的基础耐药性,导致许多药效标志物难以应用于临床实践。为评估肿瘤细胞系的基础耐药性水平及其与临床药效的相关性,本研究以48种结直肠癌(colorectal cancer,CRC)细胞系为例,通过计算265种药物IC50值之间的相关性系数,以每种CRC细胞系对上述药物IC50的中值构建可反映基础耐药性水平的评估指标MIC50,并识别出表达值与MIC50显著正相关的基因。然后基于样本内基因表达值的相对大小秩序关系构建临床CRC组织样本的基础耐药评分模型。结果表明:在药物两两间IC50的相关系数中,有99%以上呈显著正相关(FDR<0.05),证明CRC细胞系存在基础耐药性特征;与MIC50显著相关602个基因,富集到4个与肿瘤耐药密切相关的功能模块。根据5368个MIC50相关基因对,筛选出一个由21个基因对组成的5-FU联合用药评分模型,卡方检验结果表明患者基础耐药性水平的高低与用药后的响应信息显著相关,生存分析显示低分组患者比高分组患者预后更好。本研究结果为CRC联合化疗耐药机制的研究及临床个体化用药提供了一定的理论依据。

Cancer cell line models are widely used for testing drug sensitivity and in screening for drug resistance markers.However,the general level of drug resistance in cancer cell lines is often ignored by researchers,making it difficult to apply many drug efficacy markers in clinical practice.In this study,we examined 48 colorectal cancer(CRC)cell lines to calculate the correlation coefficients between the IC50 values for 265 drugs.The general drug resistance evaluation index MIC50 was constructed using the median value of 265 drugs’IC50 values.Genes with positively correlated expression values and a MIC50 which rose to significance were selected for further study.To analyze the effect of general drug resistance on the response status and prognosis in CRC patients,the general drug resistance scoring model was established based on within-sample relative expression orderings of gene pairs.The results demonstrate that more than 99%of the IC50 correlation coefficients of 265 drugs were significantly positive(FDR<0.05),indicating that CRC cell lines possessed general drug resistance characteristics.Furthermore,we identified 602 general drug resistance related genes,and by using Metascape,we identified four functional modules closely related to tumor resistance.A scoring model of 5-FU-based general drug resistance levels consisting of 21 gene pairs was built.After performingχ2 test,we found that the general drug resistance level in CRC patients was significantly correlated with the response information after accepting 5-FU-based combination drug therapy.Survival analysis showed that the low scoring cohort of patients had a better prognosis than the higher scoring cohort,indicating that the level of basic drug resistance was closely related to the prognosis and drug response status in these patients.These results provide basic theoretical support for further research on the mechanism of combined chemotherapy resistance and the individualized regimen of clinical drug use in patients with CRC.