Editors' ChoiceCancer therapy

New connections: Ewing’s sarcoma’s driver is its Achilles’ heel

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Sci. Signal.  24 Apr 2018:
Vol. 11, Issue 527, eaat9379
DOI: 10.1126/scisignal.aat9379

Several studies identify drug combinations that target or exploit the EWS-FLI1 fusion protein to kill Ewing’s sarcoma cells.

Ewing’s sarcoma is a cancer that arises in the bones and surrounding soft tissues (such as cartilage and nerves) and most commonly affects children and adolescents. Ewing’s sarcoma is often caused by a chimeric fusion between the transcription factor EWS and the mRNA splicing protein FLI1 (forming EWS-FLI1). Chemotherapy is a standard treatment for Ewing’s sarcoma, but toxicity limits dosing and hence its efficacy. Identifying ways to more effectively and selectively target Ewing’s sarcoma cells is critical to improving clinical outcomes for patients. Three studies show how the fusion protein may provide a unique opportunity for tumor-selective, low-toxicity therapies. Gorthi et al. discovered that EWS-FLI1 altered damage-induced transcription, increased replication stress, and impaired homologous recombination; hence, potentially conferring BRCA-deficiency–like vulnerabilities (such as sensitivity to PARP inhibitors) to Ewing’s sarcoma cells. Indeed, Iniguez et al. found that inhibitors of the kinase CDK12 (such as THZ531) further impaired DNA damage repair and induced apoptosis in EWS-FLI1–positive Ewing’s sarcoma cells. Combining THZ531 with PARP inhibitors was synergistic, more potently inducing tumor cell death in cultured cells and in a mouse model of patient-derived Ewing’s sarcoma, without detectable hematopoietic toxicity.

Rather than exploit a vulnerability that the fusion protein causes, one effective strategy may be to target it directly. In the archives of Science Signaling, Zöllner et al. discovered synergy between a chemical inhibitor of EWS-FLI1 (YK-4-279) and the chemotherapy vincristine. YK-4-279 decreased the EWS-FLI1–dependent expression of microtubule stability proteins and of a ubiquitin ligase, which increased the amount of the cell cycle arrest protein cyclin B1, thus promoting mitotic arrest. Ewing’s sarcoma cells were sensitive to the drug alone. However, the drug also decreased the amount of alternatively spliced, anti-apoptotic BCL2 family proteins, altogether poising cells for apoptosis upon exposure to vincristine. The combination blocked tumor growth and induced tumor regression in mice at doses of each drug that had no effects alone. These studies advance our understanding of Ewing’s sarcoma pathology and identify potentially new, selective, and less toxic therapeutic strategies for patients.

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