Abstract
BackgroundThe treatment of Ewing sarcoma, an aggressive bone and soft tissue sarcoma, is associated with suboptimal outcomes and significant side-effects. Consequently, there is an urgent need to identify novel therapies that will improve outcomes for children and adults with Ewing sarcoma tumors while also decreasing treatment-related toxicities.MethodsWe analyzed data from the PRISM drug repurposing screen, which tested the activity of 4518 drugs across 578 cancer cell lines, to identify drugs that selectively inhibit the growth of Ewing sarcoma cell lines. We then tested the effects of a top hit from the screen on cell proliferation, cell cycle progression, and activation of the DNA damage pathway using Ewing sarcoma cell lines. We also used a CRISPR/Cas9 gene knockout approach to investigate the role of Schlafen 11 (SLFN11), a restriction factor for DNA replication stress that is overexpressed in Ewing sarcoma tumors, in mediating the sensitivity of Ewing sarcoma cells to the drug.ResultsWe found that eltrombopag, an FDA-approved thrombopoietin-receptor agonist (TPO-RA) that is currently being evaluated as a treatment for chemotherapy-induced thrombocytopenia, inhibits the growth of Ewing sarcoma cell lines in vitro in proliferation and colony formation assays. However, from a mechanistic standpoint, the thrombopoietin receptor is not expressed in Ewing sarcoma cells and we show that eltrombopag impairs DNA replication and causes DNA damage in Ewing sarcoma cells by chelating iron, a known “off-target” effect of the drug. We also found that the sensitivity of Ewing sarcoma cells to eltrombopag is mediated, in part, by SLFN11, which regulates the cellular response to DNA replication stress.ConclusionsEwing sarcoma cell lines are sensitive to eltrombopag and this drug could improve outcomes for patients with Ewing sarcoma tumors by both targeting the tumor, via chelation of iron and inhibition of DNA replication, and reducing chemotherapy-induced thrombocytopenia, via stimulation of the thrombopoietin receptor.
Highlights
The treatment of Ewing sarcoma, an aggressive bone and soft tissue sarcoma, is associated with suboptimal outcomes and significant side-effects
From a mechanistic standpoint, we show that eltrombopag impairs DNA replication and causes DNA damage in Ewing sarcoma cells. These results suggest that eltrombopag could have a dual role in the treatment of Ewing sarcoma tumors by both inhibiting tumor growth, via iron chelation and induction of DNA replication stress, and reducing chemotherapy-induced myelosuppression, via stimulation of the thrombopoietin receptor
We noted that eltrombopag (ELT), a thrombopoietin receptor (MPL) agonist, was a top hit in the screen and demonstrated similar selectivity for the Ewing sarcoma cell lines as the PARP inhibitors, which was unexpected because MPL proto-oncogene (MPL) is not expected to be expressed in sarcoma cells [9]
Summary
The treatment of Ewing sarcoma, an aggressive bone and soft tissue sarcoma, is associated with suboptimal outcomes and significant side-effects. There is an urgent need to identify novel therapies that will improve outcomes for children and adults with Ewing sarcoma tumors while decreasing treatment-related toxicities. Ewing sarcoma is an aggressive bone and soft tissue cancer that occurs primarily in children and young adults [1, 2]. Waters et al BMC Cancer (2020) 20:1171 with Ewing sarcoma [5] Despite this treatment with intensive chemotherapy, the outcomes for children and adults with Ewing sarcoma remain suboptimal. There is an unmet need to identify novel therapeutic approaches to treat Ewing sarcoma that will both improve outcomes and decrease treatment-related toxicities. We used a stem cell model of Ewing sarcoma and a geneexpression based screening approach to identify that Ewing sarcoma tumors are sensitive in vitro and in vivo to iron chelators [7]
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