Ovarian cancer is one of the most lethal gynecological cancers worldwide, with approximately 70% of cases diagnosed in advanced stages. This late diagnosis results from the absence of early warning symptoms and is associated with an unfavorable prognosis. A standard treatment entails a combination of primary chemotherapy with platinum and taxane agents. Tumor recurrence following first-line chemotherapy with Carboplatin and Paclitaxel is detected in 80% of advanced ovarian cancer patients, with disease relapse occurring within 2 years of initial treatment. Platinum-resistant ovarian cancer is one of the biggest challenges in treating patients. Second-line treatments involve PARP or VEGF inhibitors. Identifying novel biomarkers and resistance mechanisms is critical to overcoming resistance, developing newer treatment strategies, and improving patient survival. In this study, we have determined that low Caspase-8 expression in ovarian cancer patients leads to poor prognosis. High-Grade Serous Ovarian Cancer (HGSOC) cells lacking Caspase-8 expression showed an altered composition of the RNA Polymerase II-containing transcriptional elongation complex leading to increased transcriptional activity. Caspase-8 knockout cells display increased BRD4 expression and CDK9 activity and reduced sensitivities to Carboplatin and Paclitaxel. Based on our work, we are proposing three potential therapeutic approaches to treat advanced ovarian cancer patients who exhibit low Caspase-8 expression and resistance to Carboplatin and/or Paclitaxel—combinations of (1) Carboplatin with small-molecule BRD4 inhibitors; (2) Paclitaxel with small-molecule BRD4 inhibitors, and (3) small-molecule BRD4 and CDK9 inhibitors. In addition, we are also proposing two predictive markers of chemoresistance—BRD4 and pCDK9.
卵巢癌是全球致死率最高的妇科恶性肿瘤之一，约70%的病例确诊时已属晚期。由于缺乏早期预警症状，晚期诊断导致患者预后不良。标准治疗方案以铂类和紫杉烷类药物联合化疗为基础。在接受卡铂与紫杉醇一线化疗的晚期卵巢癌患者中，80%会出现肿瘤复发，且多在初始治疗后两年内发生。铂类耐药性卵巢癌是目前临床治疗面临的最大挑战之一。二线治疗方案主要采用PARP抑制剂或VEGF抑制剂。识别新型生物标志物及耐药机制对于克服耐药性、开发新型治疗策略及提高患者生存率至关重要。本研究发现，卵巢癌患者中Caspase-8低表达与不良预后相关。在缺乏Caspase-8表达的高级别浆液性卵巢癌细胞中，RNA聚合酶II转录延伸复合物的组成发生改变，导致转录活性增强。Caspase-8敲除细胞表现出BRD4表达上调、CDK9活性升高，并对卡铂和紫杉醇的敏感性降低。基于研究结果，我们针对Caspase-8低表达且对卡铂和/或紫杉醇耐药的晚期卵巢癌患者提出三种潜在治疗策略：（1）卡铂联合小分子BRD4抑制剂；（2）紫杉醇联合小分子BRD4抑制剂；（3）小分子BRD4与CDK9抑制剂联合使用。此外，我们还提出BRD4和pCDK9可作为化疗耐药性的两项预测标志物。
肿瘤(癌症)患者之家