Abstract
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.
Highlights
Soft tissue sarcoma (STS) originating from mesenchymal cells is a rare neoplasm that accounts for around 1% of all adult malignancies[1]
We examined the expression of p-AKT(S473) protein levels in r1/r2-HT1080 and r1/r2-SK-LMS-1 cells by western blotting to confirm the array data
P-AKT levels were up-regulated, in a dose-dependent fashion, by eribulin treatment for 48 h in parental HT1080, SK-LMS-1 and SW872 cell lines (Fig. 2B). These results indicated that eribulin resistance in STS cells may be associated with the phosphorylation of AKT(S473) triggered by eribulin
Summary
Soft tissue sarcoma (STS) originating from mesenchymal cells is a rare neoplasm that accounts for around 1% of all adult malignancies[1]. Exploring the mechanisms of resistance to eribulin may lead to creating new treatment strategies for UM-STS. We performed phospho-protein arrays with HT1080 and eribulin resistant HT1080 cell lines to investigate the molecular mechanisms of eribulin resistance in STS cells. This assay revealed that p-AKT levels were up-regulated by eribulin treatment. These observations prompted us to assess the cytotoxicity of eribulin plus AKT inhibitor and whether this combination treatment can overcome eribulin resistance in STS cells. A combination of the AKT inhibitor, MK-2206, with eribulin resulted in synergistically induced G1 or G2/M arrest, followed by apoptosis in STS cells. Our findings provide a clinical framework for using MK-2206 with eribulin to treat patients with UM-STS
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