Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Cancer Res. 2012 Apr 1;72(7):1608-13. doi: 10.1158/0008-5472.CAN-11-3648. Epub 2012 Jan 27.
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.
尤文氏肉瘤家族肿瘤 (ESFT) 是指具有侵袭性的恶性肿瘤，这些肿瘤通常存在特征性的 EWS-FLI1 或 EWS-ERG 基因组融合。在这里，我们报告这些融合产物与 DNA 损伤反应蛋白和转录核心调节剂 PARP-1 相互作用。ESFT 细胞、原发肿瘤异种移植物和肿瘤转移都对 PARP1 抑制剂高度敏感。在 EWS-FLI1 驱动的尤文肉瘤异种移植模型中，将 PARP1 抑制剂添加到二线化疗药物替莫唑胺中，导致所有治疗肿瘤完全缓解。机制研究表明，在 ESFT 细胞系中，PARP1 抑制增强了由 EWS-FLI1 或 EWS-ERG 融合基因表达诱导的 DNA 损伤。值得注意的是，EWS-FLI1 融合基因以正反馈环的形式发挥作用，维持 PARP1 的表达，这是 EWS-FLI 介导的转录所必需的，从而加强了癌基因依赖性对 PARP-1 抑制的敏感性。总之，我们的研究结果为靶向 EWS-FLI1:PARP1 交叉作为一种治疗策略提供了强有力的临床前依据，以改善尤文氏肉瘤家族肿瘤的治疗效果。
