Research ArticlePharmacology

Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2-M cell cycle arrest and enhanced vincristine sensitivity in Ewing’s sarcoma

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Sci. Signal.  03 Oct 2017:
Vol. 10, Issue 499, eaam8429
DOI: 10.1126/scisignal.aam8429

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A multipronged attack on Ewing’s sarcoma

Chemotherapy is a standard treatment for Ewing’s sarcoma (ES), but toxicity limits dosing and hence its efficacy. Some ES tumors are driven by the oncogenic fusion protein EWS-FLI1, a transcription factor and mRNA splicing protein that can be inhibited by the drug YK-4-279. Zöllner et al. found that YK-4-279 sensitized ES cells to the chemotherapeutic drug vincristine in ways that converged on mitotic catastrophe. The drug 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. The drug also decreased the amount of alternatively spliced, antiapoptotic 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. Thus, this drug combination might be effective and might have less toxicity in ES patients.