American Association for Cancer Research
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Supplementary Figure 6 from PARP-1 Inhibition as a Targeted Strategy to Treat Ewing's Sarcoma

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journal contribution
posted on 2023-03-30, 21:23 authored by J. Chad Brenner, Felix Y. Feng, Sumin Han, Sonam Patel, Siddharth V. Goyal, Laura M. Bou-Maroun, Meilan Liu, Robert Lonigro, John R. Prensner, Scott A. Tomlins, Arul M. Chinnaiyan

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Ewing's sarcoma family of tumors (ESFT) refers to aggressive malignancies which frequently harbor characteristic EWS-FLI1 or EWS-ERG genomic fusions. Here, we report that these fusion products interact with the DNA damage response protein and transcriptional coregulator PARP-1. ESFT cells, primary tumor xenografts, and tumor metastases were all highly sensitive to PARP1 inhibition. Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete responses of all treated tumors in an EWS-FLI1–driven mouse xenograft model of ESFT. Mechanistic investigations revealed that DNA damage induced by expression of EWS-FLI1 or EWS-ERG fusion genes was potentiated by PARP1 inhibition in ESFT cell lines. Notably, EWS-FLI1 fusion genes acted in a positive feedback loop to maintain the expression of PARP1, which was required for EWS-FLI–mediated transcription, thereby enforcing oncogene-dependent sensitivity to PARP-1 inhibition. Together, our findings offer a strong preclinical rationale to target the EWS-FLI1:PARP1 intersection as a therapeutic strategy to improve the treatment of ESFTs. Cancer Res; 72(7); 1608–13. ©2012 AACR.

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