Abstract 1075: JQ1 induces DNA damage, inhibits expression of DNA repair proteins, and synergizes with PARP inhibitors in pancreatic cancer cells

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. PDAC is a highly aggressive tumor with a 5-year survival of <6%. Surgery remains the only curative treatment for PDAC patients, but only 20% of newly diagnosed patients have resectable disease. The remaining 80% present with locally advanced or metastatic disease, and receive systemic chemotherapy with gemcitabine. The median survival of this patient population is ~6 months. Development of more effective therapy for this chemorefractory disease is imperative. The goal of the current study was to develop effective combination therapy for PDAC by identifying agents that might be combined with the BET bromodomain inhibitor JQ1, which we have shown to inhibit the growth in vivo of PDAC patient derived xenografts (PDX). Expression profile analysis of tumors from vehicle control and JQ1 treated mice revealed that JQ1 inhibited the expression of multiple gene products involved in DNA repair. Notably, JQ1 inhibited expression of DNA double-strand break (DSB) repair proteins BRCA2 and Ku80. Immunohistochemical staining confirmed down-regulation of expression of both proteins in tumors of mice treated with JQ1. Further, immunoblot and immunofluorescence analyses demonstrated that decreased expression of BRCA2 and Ku80 was coincident with increased levels of DNA damage, as reflected by expression of the DNA DSB marker gamma-H2AX. Data generated in vivo in three independent PDX models corroborated in vitro data generated using pancreatic cancer cell lines BxPC3 and Panc1. The data suggest that JQ1 induces DNA damage by inhibiting DNA repair. Because DNA repair deficiency sensitizes cells to PARP inhibitors, we hypothesized that JQ1-induced DNA repair deficiency would sensitize PDAC cells to PARP inhibitors. To address this hypothesis, we exposed Panc1 and BxPC3 to JQ1 or to a PARP 1/2 inhibitor (veliparib or olaparib) or to the combinations, and assessed the efficacy of each. Growth inhibition data, analyzed using Compusyn software and reported as combination indices, demonstrated that the combinations of JQ1 + veliparib or olaparib exert synergistic cytotoxicity. Further, the combination of JQ1 + a PARP inhibitor increased the accumulation of DNA damage in vitro, compared to either agent alone. We conclude that JQ1 induces DNA damage due at least in part to DNA repair deficiency, and propose that this mechanism sensitizes PDAC cells to PARP inhibitors. Citation Format: Aubrey Lynn Miller, Tracy Gamblin, Leona Council, Robert van Waardenburg, Eddy Yang, James Bradner, Karina Yoon. JQ1 induces DNA damage, inhibits expression of DNA repair proteins, and synergizes with PARP inhibitors in pancreatic cancer cells [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 1075. doi:10.1158/1538-7445.AM2017-1075