Uridine Cytidine Kinase 2 as a Potential Biomarker for Treatment with RX-3117 in Pancreatic Cancer
Uridine Cytidine Kinase 2 as a Potential Biomarker for Treatment with RX-3117 in Pancreatic Cancer
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DOI：
10.21873/anticanres.13508
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发表时间：
2019-07-01
影响因子：
2
通讯作者：
Peters, Godefridus J.
中科院分区：
文献类型：
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作者：
El Hassouni, Btissame;Infante, Jessica;Peters, Godefridus J.
背景/目的：新型胞苷类似物RX-3117被尿苷-胞苷激酶2(UCK2)激活，在胰腺癌和膀胱癌IIa期研究中显示出令人鼓舞的活性。在这项研究中，我们强调了UCK2作为选择RX-3117治疗患者的生物标志物的潜在作用。患者和方法：应用荷兰阿姆斯特丹AMC肿瘤基因组学部开发的在线基因组学分析和可视化平台R2，研究UCK2-mRNA与胰腺癌患者总生存期的关系，同时采用免疫组织化学方法检测独立胰腺癌患者胰腺癌福尔马林固定石蜡包埋切片中UCK2蛋白的表达。同时检测Suit-2、PANC-1和PDAC-3的mRNA表达。最后，采用磺胺类若丹明B细胞毒试验检测RX-3117对药物的敏感性。结果：计算机数据显示，胰腺癌患者UCK2-mRNA的高表达与总生存期缩短有关。此外，UCK2蛋白在21/25例患者中高表达，平均表达时间明显缩短。总生存期(8.4月比34.3月，p=0.045)。RX-3117对RX-3117的敏感性在0.6~11mU之间。结论：胰腺癌细胞对药物可达的RX-3117浓度敏感，UCK2可作为患者治疗选择的生物标志物。
Background/Aim: The novel cytidine analog RX-3117, which is activated by uridine-cytidine kinase 2 (UCK2), shows encouraging activity in pancreatic and bladder cancer Phase IIa studies. In this study we highlight the potential role of UCK2 as a biomarker for selecting patients for RX-3117 treatment. Patients and Methods: The online genomics analysis and visualization platform, R2, developed by the Oncogenomics department at the AMC (Amsterdam, The Netherlands) was used for in silico UCK2-mRNA correlation with overall survival of pancreatic cancer patients, while UCK2 protein expression was evaluated by immunohistochemistry on pancreatic tumor formalin-fixed-paraffin-embedded sections from independent pancreatic cancer patients. mRNA expression was also determined for SUIT-2, PANC-1 and PDAC-3. Lastly, the drug sensitivity to RX-3117 was investigated using the Sulforhodamine-B cytotoxicity assay. Results: The in silico data showed that a high UCK2-mRNA expression was correlated with a shorter overall survival in pancreatic cancer patients. Moreover, UCK2 protein expression was high in 21/25 patients, showing a significantly shorter mean. Overall Survival (8.4 versus 34.3 months, p=0.045). Sensitivity to RX-3117 varied between 0.6 and 11 mu M. Conclusion: Pancreatic cancer cells are sensitive to pharmacologically achievable RX-3117 concentrations and UCK2 might be exploited as a biomarker for patient treatment selection.