A novel mutation panel for predicting etoposide resistance in small-cell lung cancer
A novel mutation panel for predicting etoposide resistance in small-cell lung cancer
复制标题
用于预测小细胞肺癌依托泊苷耐药性的新型突变组合
DOI：
10.2147/dddt.s205633
复制
发表时间：
2019-01-01
影响因子：
4.8
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Qiu, Zhengang;Lin, Anqi;Zhang, Jian
目的以依托泊苷（etoposide）和顺铂（cisplatin，EP）为基础的铂类化疗是广泛期小细胞肺癌（extensive-stage small-cell lung cancer，ES-SCLC）治疗的基石。尽管小细胞肺癌对化疗具有明显的初始敏感性，但EP方案在临床实践中不能避免耐药的出现。随着近年来新的化疗方案的兴起以及ES-SCLC对EP方案的原发性耐药或不敏感，希望能够识别耐药或不敏感的ES-SCLC患者。方法采用美国癌症药物敏感性基因组计划（GDSC）提供的SCLC细胞株的测序和药敏数据。分析了54种SCLC细胞系对依托泊苷的敏感性数据，并根据GDSC定义的IC 50值区分依托泊苷敏感细胞系和依托泊苷耐药细胞系。对所有突变和突变组合进行ROC曲线分析，以选择预测依托泊苷耐药性的最佳组。结果依托泊苷耐药的ROC曲线分析显示，CSMD 3突变对依托泊苷耐药的影响最大，CSMD 3/PCLO/RYR 1/EPB 41 L3突变预测依托泊苷耐药的准确性最高，曲线下面积为0.804（95%可信区间：0.679- 0.930，P <0.001）。结论CSMD 3、EPB 41 L3、PCLO和RYR 1四个基因组合可以准确预测足叶乙甙的敏感性。这些发现为对依托泊苷耐药或不敏感的ES-SCLC患者的整体治疗提供了新的见解。
Purpose Platinum-based chemotherapy, consisting of etoposide and cisplatin (EP), has been the cornerstone of therapy for extensive-stage small-cell lung cancer (ES-SCLC) for decades. Despite the marked initial sensitivity of SCLC to chemotherapy, EP regimens cannot avoid the emergence of drug resistance in clinical practice. With the rise of new chemotherapy regimens in recent years and the primary resistance or insensitivity of ES-SCLC to EP regimens, it is desirable to be able to identify patients with resistant or insensitive ES-SCLC. Methods The sequencing and drug sensitivity data of SCLC cell lines were provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC). The data regarding sensitivity to etoposide of 54 SCLC cell lines were analyzed, and etoposide-sensitive cell lines and etoposide-resistant cell lines were differentiated according to the IC50 values defined by the GDSC. ROC curve analysis was performed on all mutations and combinations of mutations to select the optimal panel to predict resistance to etoposide. Results ROC analysis of etoposide resistance revealed that the most significant single gene mutation indicating resistance to etoposide was CSMD3, and the accuracy of predicting resistance to etoposide proved to be the highest when there was any mutation in CSMD3/PCLO/RYR1/EPB41L3, area under the curve =0.804 (95% confidence interval: 0.679–0.930,P<0.001). Conclusion This study found that a panel with four genes (CSMD3, EPB41L3, PCLO, and RYR1) can accurately predict sensitivity to etoposide. These findings provide new insights into the overall treatment for patients with ES-SCLC that is resistant or insensitive to etoposide.