Abstract 953: Mechanistic rationale for inhibition of Poly(ADP-Ribose) Polymerase in ETS gene fusion positive prostate cancer

Abstract

Abstract Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers including Ewing's sarcoma, acute myeloid leukemia, and epithelial tumors such as prostate cancer. However, transcription factors like the ETS genes have been notoriously difficult to target therapeutically. In fact, while approximately 50% of all prostate cancers harbor ETS gene fusions, the most common variant fuses an androgen regulated promoter and the 5’-UTR of TMPRSS2 to the second exon of ERG resulting in the pathogenic overexpression of a slightly truncated ERG transcription factor. Here, we use IP-mass spectrometry to characterize the ETS protein interactome in prostate cancer. We show that the TMPRSS2:ERG gene fusion product interacts with the enzymes poly(ADP-ribose)polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs) in a DNA-independent manner in both prostate cancer cells and tissues. ETS gene fusion-mediated transcription of several target genes including the invasion associated gene EZH2 requires both PARP1 and DNA-PKcs expression and activity. Likewise, cell invasion driven by ETS gene overexpression is inhibited by small molecule inhibitors or siRNA against these enzymes in matrigel coated transwell invasion assays (in vitro) as well as chicken chorioallantoic membrane intravasation and metastasis assays (in vivo). Importantly, pharmacological inhibition of PARP1 selectively inhibited the growth of 4 ETS positive, but not 5 ETS negative, prostate cancer cell xenografts. This analysis includes several prostate cancer cell lines, an isogenic model of hormone refractory prostate cancer and primary human tumors that were serially grown in mice. Finally, we find that TMPRSS2:ERG gene fusion overexpression leads to increased DNA double strand breaks as assessed by gamma-H2A.X staining and COMET assays. This DNA damage is then potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2-deficiency.Thus, we propose that the ETS:PARP1 interaction axis may represent a novel target for therapeutic intervention in cancers with ETS gene fusions and that future clinical trials will help determine if this subgroup of patients preferentially benefits from the addition of PARP inhibitor therapy. Moreover, our study suggests that inhibition of co-factors necessary for function may represent a new paradigm of treatment for malignancies driven by oncogenic transcription factors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 953. doi:10.1158/1538-7445.AM2011-953