EXO1 Facilitates MiDAS and Prevents Genome Instability and Cell Death in Ewing Sarcoma
Olmedo-Pelayo, J.; Lobo-Selma, L.; Delgado-Bellido, D.; Jordan-Perez, C.; Gilabert-Prieto, P.; Perez, M.; Geyer, F. H.; Carreno-Gonzalez, M. J.; Alonso, J.; Zheng, L.; Shen, B.; Grunewald, T. G. P.; Gomez Herreros, F.; de Alava, E.
Show abstract
Ewing sarcoma (EwS) is an aggressive malignancy driven by EWSR1::ETS fusions, predominantly EWSR1::FLI1. Previous efforts using both direct and indirect approaches to target these chimeric oncoproteins have yielded limited clinical benefit. Although EWSR1::FLI1 is a well-known source of replication stress and genome instability, targeting DNA damage response (DDR) factors that mitigate these effects remain poorly understood. Here, we identified a marked dependency of EwS cells on exonuclease 1 (EXO1). We demonstrate that EXO1 is essential for EwS cell survival and tumor growth, highlighting its potential as a novel therapeutic target. Intriguingly, we unveil that EXO1 loss impairs mitotic DNA synthesis (MiDAS), promoting EWSR1::FLI1-associated genome instability and cell death. Collectively, our results support the idea that targeting DDR factors, which counteract replication stress and/or DNA damage induced by fusion oncoproteins, represents a promising therapeutic option for EwS.
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