PDF(Pubmed)
Abstract：
Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.
摘要：
三阴性乳腺癌（TNBC）仍然是最致命的乳腺癌亚型，其特点是对当前化疗的应答率很低，并且缺乏其他有效的治疗选择。虽然大约30％的患者对基于蒽环类和紫杉烷的标准治疗化疗方案反应良好，大多数患者的临床结果改善有限，强调了在TNBC中提高蒽环类/紫杉烷类化疗有效性的策略的迫切需要。在这项研究中,我们报道了DNA-PK抑制剂的潜力，peposertib,为了提高拓扑异构酶II（TOPOII）抑制剂的有效性，尤其是蒽环类药物,在TNBC。我们的体外研究证明了peposertib与多柔比星的协同抗增殖活性，多种TNBC细胞系中的表柔比星和依托泊苷。下游分析显示在联合治疗下ATM依赖性代偿信号和p53途径激活的诱导。这些体外发现通过在携带皮下植入肿瘤的小鼠中观察到的明显的抗肿瘤作用得到证实。我们建立了一种耐受性良好的临床前治疗方案，将peposertib与聚乙二醇化脂质体多柔比星（PLD）相结合，并在体内细胞系来源和患者来源的TNBC异种移植模型中显示出强大的抗肿瘤功效。一起来看,我们的研究结果提供了证据，证明与peposertib联合治疗有可能增强蒽环类/TOPOII型化疗的疗效，它为改善TNBC患者的治疗结果提供了一个有希望的策略。
