Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication
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RESEARCH ARTICLE
Open Access
Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication Torin Waters, Kelli L. Goss, Stacia L. Koppenhafer, William W. Terry and David J. Gordon*
Abstract Background: The 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. Methods: We 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. Results: We 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. Conclusions: Ewing 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. Keywords: Ewing sarcoma, Eltrombopag, Iron chelation
Background Ewing sarcoma is an aggressive bone and soft tissue cancer that occurs primarily in children and young adults [1, 2]. The driver oncogene in most Ewing sarcoma tumors, EWS-FLI1, was identified over two decade ago, but directly targeting this oncogene has proven * Correspondence: [email protected] Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Iowa, 25 S Grand Avenue, Iowa City, Iowa 52242, USA
challenging [3, 4]. Consequently, the current therapy for Ewing sarcoma consists of cytotoxic chemotherapy in combination with surgery and/or radiation therapy. The AEWS0031 clinical trial (2001–2005) showed that chemotherapy intensification through interval comp
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