BRCA1/ATF1-Mediated Transactivation is Involved in Resistance to PARP Inhibitors and Cisplatin.
BRCA1/ATF1-Mediated Transactivation is Involved in Resistance to PARP Inhibitors and Cisplatin.
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DOI：
10.1158/2767-9764.crc-21-0064
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发表时间：
2021-11
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同源重组（HR）缺陷细胞通过合成致死效应对PARP抑制剂敏感。我们以前开发了一种HR活性测定，称为位点特异性HR活性测定（ASHRA）。在这里，我们通过ASHRA评估了30种BRCA 1错义变体的HR活性，发现几种BRCA 1变体显示出中等的HR活性，这是我们以前使用常规方法进行的分析无法清楚识别的。通过ASHRA测量的HR活性与奥拉帕尼的敏感性显著相关。然而，表达严重HR缺陷型BRCA 1-C61 G变体的细胞对奥拉帕尼耐药，耐药依赖于转录激活因子1（ATF 1）的高表达，该因子与BRCA 1结合并激活靶基因的转录以调节细胞增殖。BRCA 1-C61 G变体与ATF 1结合，并刺激ATF 1介导的反式激活，类似于野生型BRCA 1。ATF 1的高表达赋予了对奥拉帕尼和顺铂的抗性，从而激活BRCA 1/ATF 1介导的转录，而不影响BRCA 2敲低或RAD 51敲低细胞中的HR活性，但不影响BRCA 1敲低细胞中的HR活性。这些结果表明，ASHRA是一种有用的方法来评估HR活动在细胞中，并预测敏感性PARP抑制剂。ATF 1的表达水平可能是PARP抑制剂和铂类药物对具有BRCA 1-C61 G变异或非BRCA 1 HR因子（如BRCA 2和RAD 51）改变的HR缺陷肿瘤的作用的重要生物标志物。ASHRA可以评估细胞HR活性，预测对PARP抑制剂的敏感性。ATF 1的高表达水平可预测BRCAness肿瘤对PARP抑制剂和铂类药物的耐药性，而非BRCA 1 HR因子的改变可预测BRCAness肿瘤对PARP抑制剂和铂类药物的耐药性。
Homologous recombination (HR)-deficient cells are sensitive to PARP inhibitors through a synthetic lethal effect. We previously developed an HR activity assay named Assay of Site-Specific HR Activity (ASHRA). Here, we evaluated the HR activity of 30 missense variants of BRCA1 by ASHRA and found that several BRCA1 variants showed intermediate HR activity, which was not clearly discerned by our previous analyses using a conventional method. HR activity measured by ASHRA was significantly correlated with sensitivity to olaparib. However, cells expressing the severely HR-deficient BRCA1-C61G variant were resistant to olaparib, and resistance was dependent on high expression of activating transcription factor 1 (ATF1), which binds to BRCA1 and activates the transcription of target genes to regulate cell proliferation. The BRCA1-C61G variant bound to ATF1 and stimulated ATF1-mediated transactivation similar to wild-type BRCA1. High expression of ATF1 conferred resistance to olaparib and cisplatin activating BRCA1/ATF1-mediated transcription without affecting HR activity in BRCA2-knockdown or RAD51-knockdown cells, but not in BRCA1-knockdown cells. These results suggest that ASHRA is a useful method to evaluate HR activity in cells and to predict the sensitivity to PARP inhibitors. The expression level of ATF1 might be an important biomarker of the effect of PARP inhibitors and platinum agents on HR-deficient tumors with the BRCA1-C61G variant or alteration of non-BRCA1 HR factors such as BRCA2 and RAD51. ASHRA could evaluate HR activity in cells and predict the sensitivity to PARP inhibitors. High expression level of ATF1 may predict the resistance of BRCAness tumors with alterations of non-BRCA1 HR factors to PARP inhibitors and platinum agents.