PARP-1 Inhibition as a Targeted Strategy to Treat Ewing's Sarcoma

被引：210

作者：

Brenner, J. Chad ^{[1
,2
,5
]}

Feng, Felix Y. ^{[1
,3
,7
]}

Han, Sumin ^{[3
]}

Patel, Sonam ^{[1
,2
]}

Goyal, Siddharth V. ^{[1
,2
]}

Bou-Maroun, Laura M. ^{[1
,2
]}

Liu, Meilan ^{[3
]}

Lonigro, Robert ^{[1
,2
]}

Prensner, John R. ^{[1
,2
]}

Tomlins, Scott A. ^{[1
,2
]}

Chinnaiyan, Arul M. ^{[1
,2
,4
,5
,6
,7
]}

机构：

[1] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Program Cellular & Mol Biol, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

来源：

CANCER RESEARCH | 2012年 / 72卷 / 07期

关键词：

ETS TRANSCRIPTION FACTOR; POLY(ADP-RIBOSE) POLYMERASE; PROSTATE-CANCER; BINDING; FUSION; CHROMATIN; TUMORS; GENES; CELLS;

D O I：

10.1158/0008-5472.CAN-11-3648

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C)2012 AACR.

引用

页码：1608 / 1613

页数：6

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