DNA Repair Capacity in Multiple Pathways Predicts Chemoresistance in Glioblastoma Multiforme.
DNA Repair Capacity in Multiple Pathways Predicts Chemoresistance in Glioblastoma Multiforme.
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DOI：
10.1158/0008-5472.can-16-1151
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发表时间：
2017-01-01
期刊：
影响因子：
11.2
通讯作者：
Samson LD
中科院分区：
文献类型：
--
作者：
Nagel ZD;Kitange GJ;Gupta SK;Joughin BA;Chaim IA;Mazzucato P;Lauffenburger DA;Sarkaria JN;Samson LD
癌细胞可以通过利用DNA修复途径抵抗DNA损伤治疗剂的作用，这表明癌细胞中的DNA修复能力（DRC）测量可用于识别最有可能对治疗产生反应的患者。然而，到目前为止，现有技术的局限性阻碍了这种方法在临床中的采用。我们最近开发了基于荧光的多重宿主细胞再激活（FM-HCR）测定，以测量多个途径中的DRC。在这里，我们应用了一个数学模型，在多个途径中使用DRC来预测细胞对DNA损伤剂杀伤的抵抗力。该模型使用FM-HCR和24种人类淋巴母细胞系中的药物敏感性测量开发，应用于一组12种胶质母细胞瘤患者来源的异种移植（PDX）模型，以预测胶质母细胞瘤对化疗DNA损伤剂替莫唑胺治疗的反应。这项工作表明，除了O 6-甲基鸟嘌呤DNA甲基转移酶（MGMT）活性的变化外，错配修复（MMR）、核苷酸切除修复（NER）和同源重组（HR）能力的微小变化也导致PDX模型中获得性替莫唑胺耐药，并导致替莫唑胺治疗体内原位小鼠模型后相对生存期延长减少。我们的数据表明，测量MMR，HR，NER和MGMT的组合状态比单独评估MGMT活性提供了更可靠的替莫唑胺耐药预测。
Cancer cells can resist the effects of DNA-damaging therapeutic agents via utilization of DNA repair pathways, suggesting that DNA repair capacity (DRC) measurements in cancer cells could be used to identify patients most likely to respond to treatment. However, the limitations of available technologies have so far precluded adoption of this approach in the clinic. We recently developed fluorescence-based multiplexed host cell reactivation (FM-HCR) assays to measure DRC in multiple pathways. Here we apply a mathematical model that uses DRC in multiple pathways to predict cellular resistance to killing by DNA-damaging agents. This model, developed using FM-HCR and drug sensitivity measurements in 24 human lymphoblastoid cell lines, was applied to a panel of 12 patient-derived xenograft (PDX) models of glioblastoma to predict glioblastoma response to treatment with the chemotherapeutic DNA-damaging agent temozolomide. This work showed that, in addition to changes in O6-methylguanine DNA methyltransferase (MGMT) activity, small changes in mismatch repair (MMR), nucleotide excision repair (NER), and homologous recombination (HR) capacity contributed to acquired temozolomide resistance in PDX models and led to reduced relative survival prolongation following temozolomide treatment of orthotopic mouse models in vivo. Our data indicate that measuring the combined status of MMR, HR, NER, and MGMT provided a more robust prediction of temozolomide resistance than assessments of MGMT activity alone.