Background/Objectives: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment options. The nuclear export protein XPO1 has emerged as a potential therapeutic target in cancer, but its role in TNBC has not been fully characterized. This study investigates the potential of repurposing selinexor, an FDA-approved XPO1 inhibitor, as a novel therapeutic options for TNBC.Methods: A computational drug repurposing pipeline was used to predict patient tumor responses to hundreds of drugs. We identified XPO1 inhibitors as a candidate drug and validated its efficacy on an independent patient dataset and across various TNBC cell lines. RNA-sequencing after longitudinal XPO1 inhibition and further mechanistic studies were performed to explore and confirm the leading causes of TNBC cell sensitivity to XPO1 inhibition.Results: Selinexor significantly reduce the viability of a variety of TNBC cell lines. Mechanistically, selinexor induces TNBC cell death by inhibiting the NF-kB pathway through nuclear retention of NFKBIA. This effect was consistent across multiple TNBC cell lines.Conclusions: XPO1 inhibitors show promise as targeted therapies for TNBC patients. New mechanistic insight into the causes leading to TNBC sensitivity to XPO1-inhibition-mediated cell death warrant further clinical trials to evaluate the safety and efficacy in TNBC.
背景/目的：三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌，治疗选择有限。核输出蛋白XPO1已成为癌症治疗的潜在靶点，但其在TNBC中的作用尚未完全明确。本研究旨在探讨重新利用美国食品药品监督管理局（FDA）已批准的XPO1抑制剂塞利尼索（selinexor）作为TNBC新型治疗方案的潜力。 方法：采用计算药物重定位流程预测患者肿瘤对数百种药物的反应。我们确定XPO1抑制剂为候选药物，并在独立患者数据集及多种TNBC细胞系中验证其疗效。通过纵向XPO1抑制后的RNA测序及进一步机制研究，探索并确认TNBC细胞对XPO1抑制敏感性的主要成因。 结果：塞利尼索能显著降低多种TNBC细胞系的活力。机制研究表明，塞利尼索通过核滞留NFKBIA抑制NF-κB通路，从而诱导TNBC细胞死亡。该效应在多种TNBC细胞系中表现一致。 结论：XPO1抑制剂有望成为TNBC患者的靶向疗法。关于TNBC对XPO1抑制介导的细胞死亡敏感性的新机制见解，值得通过进一步临床试验评估其在TNBC治疗中的安全性与有效性。
肿瘤(癌症)患者之家