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Cancer Res. 2012 Apr 1;72(7):1608-13. doi: 10.1158/0008-5472.CAN-11-3648. Epub 2012 Jan 27.

PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma.

Author information

1
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Abstract

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.

PMID:
22287547
PMCID:
PMC3319786
DOI:
10.1158/0008-5472.CAN-11-3648
[Indexed for MEDLINE]
Free PMC Article

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