聚（ADP-核糖）聚合酶抑制剂（PARPi）被批准用于治疗 BRCA 突变乳腺癌（BC），包括三阴性 BC（TNBC）和卵巢癌（OvCa）。一个关键的挑战是确定与 PARPi 耐药性相关的因素；不过，之前的研究表明铂类药物和 PARPi 具有相似的耐药机制。使用 HTG EdgeSeq miRNA 全转录组分析 (WTA) 分析了奥拉帕尼耐药 (OlaR) 细胞系。在三种 BRCA 突变的 TNBC 细胞系中进行了功能测定。使用多个数据库进行计算机分析，包括癌症基因组图谱、基因型组织表达、癌细胞系百科全书、癌症药物敏感性基因组学和基因综合表达。在 OlaR TNBC 细胞中鉴定出高 miR-181a 水平线（p = 0.001）以及来自TNBC患者的肿瘤组织（p = 0.001）。我们假设 miR-181a 下调干扰素基因刺激剂 (STING) 和下游促炎细胞因子以介导 PARPi 耐药。 miR-181a 过表达的 BRCA1 突变 TNBC 细胞系对奥拉帕尼更具耐药性，并且 STING 和受 STING 控制的下游基因下调。源自 PARPi 抗性 TNBC 细胞系的细胞外囊泡将 miR-181a 水平转移至亲代细胞，从而赋予 PARPi 抗性并靶向 STING。在临床环境中，STING 水平与干扰素 γ (IFNG) 反应评分呈正相关 (p = 0.01)。此外，低 IFNG 反应评分与高危 HER2 阴性 BC 患者对新辅助治疗（包括 PARPi）的反应较差相关（p = 0.001）。 OlaR TNBC 细胞系对铂类药物表现出耐药性。对铂具有耐药性的 OvCa 细胞系表现出对奥拉帕尼的耐药性。敲除 miR-181a 显着提高 OvCa 细胞系中奥拉帕尼的敏感性 (p = 0.001)。miR-181a 是控制 STING 通路并驱动 TNBC 和 OvCa 中 PARPi 和铂类药物耐药性的关键因素。 miR-181a-STING 轴可用作预测 TNBC 和 OvCa 肿瘤中 PARPi 反应的潜在标志物。© 2023。作者。

Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of BRCA-mutated breast cancer (BC), including triple-negative BC (TNBC) and ovarian cancer (OvCa). A key challenge is to identify the factors associated with PARPi resistance; although, previous studies suggest that platinum-based agents and PARPi share similar resistance mechanisms.Olaparib-resistant (OlaR) cell lines were analyzed using HTG EdgeSeq miRNA Whole Transcriptomic Analysis (WTA). Functional assays were performed in three BRCA-mutated TNBC cell lines. In-silico analysis were performed using multiple databases including The Cancer Genome Atlas, the Genotype-Tissue Expression, The Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, and Gene Omnibus Expression.High miR-181a levels were identified in OlaR TNBC cell lines (p = 0.001) as well as in tumor tissues from TNBC patients (p = 0.001). We hypothesized that miR-181a downregulates the stimulator of interferon genes (STING) and the downstream proinflammatory cytokines to mediate PARPi resistance. BRCA1 mutated TNBC cell lines with miR-181a-overexpression were more resistant to olaparib and showed downregulation in STING and the downstream genes controlled by STING. Extracellular vesicles derived from PARPi-resistant TNBC cell lines horizontally transferred miR-181a to parental cells which conferred PARPi-resistance and targeted STING. In clinical settings, STING levels were positively correlated with interferon gamma (IFNG) response scores (p = 0.01). In addition, low IFNG response scores were associated with worse response to neoadjuvant treatment including PARPi for high-risk HER2 negative BC patients (p = 0.001). OlaR TNBC cell lines showed resistance to platinum-based drugs. OvCa cell lines resistant to platinum showed resistance to olaparib. Knockout of miR-181a significantly improved olaparib sensitivity in OvCa cell lines (p = 0.001).miR-181a is a key factor controlling the STING pathway and driving PARPi and platinum-based drug resistance in TNBC and OvCa. The miR-181a-STING axis can be used as a potential marker for predicting PARPi responses in TNBC and OvCa tumors.© 2023. The Author(s).