Abstract
Ewing sarcoma is a transcription factor-mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279-mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-β, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma.
Highlights
Ewing sarcoma family of tumors, which encompass traditional Ewing sarcoma of bone [1], primitive neuroectodermal tumors (PNET; refs. 2), and Askin tumor of chest wall [3,4,5], have for more than a two decades been considered to represent clinical variants of the same molecularly distinct sarcoma subtype that bears a pathognomonic EWS–ETS oncogenic fusion protein [6]
The aberrant fusion proteins, such as EWS–FLI1, are attractive targets given ubiquitous presence in Ewing sarcoma, they have remained stubbornly resistant to therapeutic intervention until recently with the development of YK-4-279
YK-4-279 is the first precision-guided drug candidate to show preclinical activity in Ewing sarcoma, which was designed to adhere to FLI1 at a putative RNA helicase A (RHA)-binding site and, in turn, downregulate transcriptional activity of the EWS–FLI1 fusion protein
Summary
Ewing sarcoma family of tumors, which encompass traditional Ewing sarcoma of bone [1], primitive neuroectodermal tumors (PNET; refs. 2), and Askin tumor of chest wall [3,4,5], have for more than a two decades been considered to represent clinical variants of the same molecularly distinct sarcoma subtype that bears a pathognomonic EWS–ETS oncogenic fusion protein [6]. 2), and Askin tumor of chest wall [3,4,5], have for more than a two decades been considered to represent clinical variants of the same molecularly distinct sarcoma subtype that bears a pathognomonic EWS–ETS oncogenic fusion protein [6]. Heretofore, referred to as Ewing sarcoma, this sarcoma subtype is a highly aggressive malignancy of adolescents and young adults [7] that is rapidly fatal without effective multimodality treatment that includes surgery and/or radiation and extensive use of systemic chemotherapy. Cytotoxic chemotherapy will remain the mainstay for treating Ewing sarcoma in the near future given its welltrodden track record of antineoplastic activity, high-throughput "-omic" technologies and paired biomarkers are enabling an era of precision medicine that, as has occurred for more common carcinomas such as breast or lung cancer, will increasingly target the unique molecular complexity linked to each patient's respective tumor. Therapies targeting the insulin-like growth factor 1 receptor (IGFIR), alone or in combination with inhibitors of mammalian target of rapamycin (mTOR), provide just one example of selective biologically targeted therapies capable of inducing striking tumor regression among a subset of Ewing sarcoma patients [12, 13]
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