Abstract LB-086: PARP-1 controls the DNA damage response by regulating E2F1 transcriptional activity

Abstract

Abstract PARP-1 holds two major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Notably, PARP-1 has been found to be a key modulator of androgen receptor (AR) function and AR-dependent phenotypes, which is a driving factor in prostate cancer (PCa) biology and therapeutic management. Recent studies indicate an unanticipated prevalence of DNA repair alterations in advanced PCa and showed that PARP-1 inhibitors (PARPi) can effectively manage of a subset of these tumors. Despite the functions of PARP-1 in DNA repair having been exploited as a therapeutic target for tumors with BRCA1/2 aberrations, factors beyond DNA repair alterations clearly play a role in the response to PARPi. Notably, in the TO-PARP trial, not all patients with DNA repair aberrations responded to PARPi; conversely, tumors lacking BRCA1/2 or other DNA repair alterations show objective response to PARPi in PCa and other tumor types. These clinical data suggest that the genetic (e.g. BRCA-ness) and pharmacologic interplay is complex in the context of PARPi. Given the preclinical and clinical data, pursuing a deeper understanding of the molecular underpinnings of PARPi action in PCa may yield significant benefit. Genome-wide transcriptional profiling in response to PARPi was performed and the PARP-1-regulated transcriptome was identified. Human tissue microarrays were utilized to quantify PARP-1 levels and activity as a function of PCa progression. Both the PARP-1-regulated transcriptome, as well as PARP-1 enzymatic activity, were found to be elevated as a function of PCa progression. Further interrogation of the PARP-1-regulated transcriptome revealed a major impact on E2F1-regulated genes, and chromatin immunoprecipitation analyses indicated that PARP-1 functions to regulate the chromatin architecture and E2F1 occupancy at E2F1 target gene loci. Most prominent among the E2F1-regulated genes responsive to PARPi were genes associated with DNA damage repair, with a particular enrichment for genes involved in homologous recombination (HR). In sum, these data indicate PARP-1 regulates the function of key oncogenic transcription factors (AR and E2F1) in PCa, and part of the effect of PARPi may be through down-regulation of DNA repair factors. Citation Format: Matthew J. Schiewer, Amy C. Mandigo, Nicolas Gordon, Fangjin Huang, Sanchaika Gaur, Shuang Zhao, Joseph Evans, Sumin Han, Theodore Parsons, Ruth Birbe, Peter McCue, Tapio Visakorpi, Ganesh Raj, Mark Rubin, Johann de Bono, Costas Lallas, Edouard Trabulsi, Leonard G. Gomella, Adam P. Dicker, Kevin Kelly, Beatrice Knudsen, Felix Feng, Karen E. Knudsen. PARP-1 controls the DNA damage response by regulating E2F1 transcriptional activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-086. doi:10.1158/1538-7445.AM2017-LB-086