Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells.
Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells.
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DOI：
10.1002/bit.26293
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发表时间：
2017-09
影响因子：
3.8
通讯作者：
Shea LD
中科院分区：
文献类型：
--
作者：
Decker JT;Hobson EC;Zhang Y;Shin S;Thomas AL;Jeruss JS;Arnold KB;Shea LD
对靶向治疗药物的耐药性的产生是癌症治疗中的一个具有挑战性的问题。发生DNA修复蛋白BRCA突变的癌症已经接受了聚(ADP-核糖)聚合酶(PARP)抑制剂的治疗，这种抑制剂针对第二种DNA修复机制，目的是诱导合成致命性。虽然这些抑制剂在临床上显示出了希望，但耐药性的发展可能会限制它们作为一种治疗方法的有效性。本研究利用TRACE技术研究BRCA突变癌细胞(HCC1937)对奥拉帕利(AZD2281)耐药的机制。观察了亲本HCC1937细胞系和两个不同抗性细胞系的TF活性，其中一个细胞系具有野生型BRCA1恢复的抗性，另一个细胞系在奥拉帕利处理48h后获得了不依赖BRCA1的抗性。用偏最小二乘判别分析(PLSDA)根据TF活性对三种细胞类型进行分类，并用网络分析探讨研究细胞对奥拉帕利的早期反应机制。Notch信号被认为是与两种奥拉帕利耐药细胞类型的耐药相关的共同途径。Western blotting证实Noch蛋白上调，并通过与伽马分泌酶抑制剂共同处理恢复了对奥拉帕利的敏感性。通过示踪剂发现Noch信号通路是导致PARP抑制剂耐药的常见途径，表明转录因子动力学在确定耐药肿瘤干预靶点方面的有效性，并为确定有效的定向化疗策略提供了一种新的方法。
The development of resistance to targeted therapeutics is a challenging issue for the treatment of cancer. Cancers that have mutations in BRCA, a DNA repair protein, have been treated with poly (ADP-ribose) polymerase (PARP) inhibitors, which target a second DNA repair mechanism with the aim of inducing synthetic lethality. While these inhibitors have shown promise clinically, the development of resistance can limit their effectiveness as a therapy. This study investigated mechanisms of resistance in BRCA-mutated cancer cells (HCC1937) to Olaparib (AZD2281) using TRACER, a technique for measuring dynamics of transcription factor (TF) activity in living cells. TF activity was monitored in the parental HCC1937 cell line and two distinct resistant cell lines, one with restored wild-type BRCA1 and one with acquired resistance independent of BRCA1 for 48 hours during treatment with Olaparib. Partial least squares discriminant analysis (PLSDA) was used to categorize the three cell types based on TF activity, and network analysis was used to investigate the mechanism of early response to Olaparib in the study cells. NOTCH signaling was identified as a common pathway linked to resistance in both Olaparib-resistant cell types. Western blotting confirmed upregulation of NOTCH protein, and sensitivity to Olaparib was restored through co-treatment with a gamma secretase inhibitor. The identification of NOTCH signaling as a common pathway contributing to PARP inhibitor resistance by TRACER indicates the efficacy of transcription factor dynamics in identifying targets for intervention in treatment-resistant cancer and provides a new method for determining effective strategies for directed chemotherapy.
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影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1039/c6ib00093b
发表时间：
2016-08-08
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
--
作者：
Peñalver Bernabé B;Shin S;Rios PD;Broadbelt LJ;Shea LD;Seidlits SK
通讯作者：
Seidlits SK
影响因子：
17.1
作者：
Beste MT;Pfäffle-Doyle N;Prentice EA;Morris SN;Lauffenburger DA;Isaacson KB;Griffith LG
通讯作者：
Griffith LG
影响因子：
7.3
作者：
Barber, Louise J.;Sandhu, Shahneen;Ashworth, Alan
通讯作者：
Ashworth, Alan