Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells
Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells
复制标题
DOI：
10.1038/s41598-019-42300-z
复制
发表时间：
2019-04-08
影响因子：
4.6
通讯作者：
Kato, Junji
中科院分区：
文献类型：
--
作者：
Hayasaka, Naotaka;Takada, Kohichi;Kato, Junji
激活的AKT通路是软组织肉瘤（STS）发病机制的基础，在一部分STS病例中，过度表达的磷酸化AKT （p-AKT）与预后不良相关。最近，一种微管动力学抑制剂埃立布林（eribulin）已被证明有效，并被批准用于晚期/转移性脂肪肉瘤和乳腺癌患者。然而，伊瑞布林耐药和/或不敏感的机制在很大程度上仍然未知。在这项研究中，我们证明了p-AKT水平的升高与STS细胞对伊瑞布林的耐药性有关。我们发现，与AKT抑制剂MK-2206联合使用，在体内和体外均能协同抑制STS细胞的生长。在机制上，伊瑞布林加MK-2206通过下调周期蛋白依赖性激酶、周期蛋白和cdc2诱导STS细胞G1或G2/M阻滞，随后发生caspase依赖性凋亡。我们的研究结果证明了p-AKT信号在STS细胞中对伊瑞布林耐药的重要性，并为开发AKT抑制剂与伊瑞布林联合治疗STS患者提供了理论依据。
An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth in vivo as well as in vitro. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.