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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
摘要：
背景：聚（ADP-核糖）聚合酶抑制剂（PARPi）被批准用于治疗BRCA突变的乳腺癌（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抗性相关的因素；尽管，先前的研究表明，铂类药物和PARPi具有相似的耐药机制。
方法:使用HTGEdgeSeqmiRNA全转录组学分析(WTA)分析Olaparib抗性(OlaR)细胞系。在三种BRCA突变的TNBC细胞系中进行功能测定。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。
结果：在OlaRTNBC细胞系（p=0.001）以及来自TNBC患者的肿瘤组织（p=0.001）中鉴定出高miR-181a水平。我们假设miR-181a下调干扰素基因刺激因子（STING）和下游促炎细胞因子以介导PARPi抗性。具有miR-181a过表达的BRCA1突变的TNBC细胞系对奥拉帕尼的抗性更强，并且在STING和STING控制的下游基因中显示出下调。源自PARPi抗性TNBC细胞系的细胞外囊泡水平转移miR-181a至亲代细胞,其赋予PARPi抗性和靶向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应答评分与高危HER2阴性BC患者对包括PARPi在内的新辅助治疗的应答较差相关(p=0.001).OlaRTNBC细胞系显示出对铂类药物的抗性。抗铂的OvCa细胞系显示出对奥拉帕尼的抗性。miR-181a基因敲除显著提高OvCa细胞系中的奥拉帕尼敏感性(p=0.001)。
结论：miR-181a是控制STING途径并驱动PARPi和铂类耐药的关键因素。miR-181a-STING轴可用作预测TNBC和OvCa肿瘤中PARPi应答的潜在标志物。
方法:使用HTGEdgeSeqmiRNA全转录组学分析(WTA)分析Olaparib抗性(OlaR)细胞系。在三种BRCA突变的TNBC细胞系中进行功能测定。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。
结果：在OlaRTNBC细胞系（p=0.001）以及来自TNBC患者的肿瘤组织（p=0.001）中鉴定出高miR-181a水平。我们假设miR-181a下调干扰素基因刺激因子（STING）和下游促炎细胞因子以介导PARPi抗性。具有miR-181a过表达的BRCA1突变的TNBC细胞系对奥拉帕尼的抗性更强，并且在STING和STING控制的下游基因中显示出下调。源自PARPi抗性TNBC细胞系的细胞外囊泡水平转移miR-181a至亲代细胞,其赋予PARPi抗性和靶向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应答评分与高危HER2阴性BC患者对包括PARPi在内的新辅助治疗的应答较差相关(p=0.001).OlaRTNBC细胞系显示出对铂类药物的抗性。抗铂的OvCa细胞系显示出对奥拉帕尼的抗性。miR-181a基因敲除显著提高OvCa细胞系中的奥拉帕尼敏感性(p=0.001)。
结论：miR-181a是控制STING途径并驱动PARPi和铂类耐药的关键因素。miR-181a-STING轴可用作预测TNBC和OvCa肿瘤中PARPi应答的潜在标志物。
