转移复发仍然是乳腺癌治疗的主要挑战。三阴性乳腺癌（TNBC）患者会出现早期复发且复发频率更高。由于TNBC缺乏特异性治疗靶点，迫切需要新的靶向治疗方法。磷酸肌醇3激酶(PI3K)/蛋白激酶B(AKT)/哺乳动物雷帕霉素靶蛋白(mTOR)通路是参与TNBC化疗耐药和生存的活性通路之一，被认为是TNBC治疗的潜在靶点。我们目前的研究确定了替格瑞洛（一种抗血小板药物）作为一种泛 PI3K 抑制剂，对 I 类 PI3K 的四种亚型具有有效的抑制活性。在临床常用剂量下，替格瑞洛对一组乳腺癌细胞表现出微弱的细胞毒性，但显着抑制人 TNBC MDA-MB-231 和 SUM-159PT 细胞的迁移、侵袭和肌动蛋白细胞骨架组织。从机制上讲，替格瑞洛通过靶向 PI3K 有效抑制 PI3K 下游 mTOR 复合物 1 (mTORC1) 和 mTORC2 信号传导，并降低上皮间质转化 (EMT) 标志物的蛋白表达。在体内，替格瑞洛显着抑制4T1荷瘤BALB/c小鼠模型和通过尾静脉注射GFP标记的MDA-MB-231细胞建立的实验性肺转移模型中的肿瘤细胞肺转移。上述数据表明，替格瑞洛可以通过靶向PI3K在体外和体内抑制TNBC的迁移和侵袭，表明替格瑞洛这种泛PI3K抑制剂可能是治疗转移性TNBC的一种有前途的治疗药物。版权所有©2024爱思唯尔公司出版。

Metastatic recurrence is still a major challenge in breast cancer treatment. Patients with triple negative breast cancer (TNBC) develop early recurrence and relapse more frequently. Due to the lack of specific therapeutic targets, new targeted therapies for TNBC are urgently needed. Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway is one of the active pathways involved in chemoresistance and survival of TNBC, being considered as a potential target for TNBC treatment. Our present study identified ticagrelor, an anti-platelet drug, as a pan-PI3K inhibitor with potent inhibitory activity against four isoforms of class I PI3K. At doses normally used in clinic, ticagrelor showed weak cytotoxicity against a panel of breast cancer cells, but significantly inhibited the migration, invasion and the actin cytoskeleton organization of human TNBC MDA-MB-231 and SUM-159PT cells. Mechanistically, ticagrelor effectively inhibited PI3K downstream mTOR complex 1 (mTORC1) and mTORC2 signaling by targeting PI3K and decreased the protein expression of epithelial-mesenchymal transition (EMT) markers. In vivo, ticagrelor significantly suppressed tumor cells lung metastasis in 4T1 tumor bearing BALB/c mice model and experimental lung metastasis model which was established by tail vein injection of GFP-labeled MDA-MB-231 cells. The above data demonstrated that ticagrelor can inhibit the migration and invasion of TNBC both in vitro and in vivo by targeting PI3K, suggesting that ticagrelor, a pan-PI3K inhibitor, might represent a promising therapeutic agent for the treatment of metastatic TNBC.Copyright © 2024. Published by Elsevier Inc.