The BET inhibitor JQ1 attenuates double-strand break repair and sensitizes models of pancreatic ductal adenocarcinoma to PARP inhibitors

Abstract

Background DNA repair deficiency accumulates DNA damage and sensitizes tumor cells to PARP inhibitors (PARPi). Based on our observation that the BET inhibitor JQ1 increases levels of DNA damage, we evaluated the efficacy of JQ1 + the PARPi olaparib in preclinical models of pancreatic ductal adenocarcinoma (PDAC). We also addressed the mechanism by which JQ1 increased DNA damage. Methods The effect of JQ1 + olaparib on in vivo tumor growth was assessed with patient-derived xenograft (PDX) models of PDAC. Changes in protein expression were detected by immunohistochemistry and immunoblot. In vitro growth inhibition and mechanistic studies were done using alamarBlue, qRT-PCR, immunoblot, immunofluorescence, ChIP, and shRNA knockdown assays. Findings Tumors exposed in vivo to JQ1 had higher levels of the DNA damage marker γH2AX than tumors exposed to vehicle only. Increases in γH2AX was concomitant with decreased expression of DNA repair proteins Ku80 and RAD51. JQ1 + olaparib inhibited the growth of PDX tumors greater than either drug alone. Mechanistically, ChIP assays demonstrated that JQ1 decreased the association of BRD4 and BRD2 with promoter loci of Ku80 and RAD51, and shRNA data showed that expression of Ku80 and RAD51 was BRD4- and BRD2-dependent in PDAC cell lines. Interpretation The data are consistent with the hypothesis that JQ1 confers a repair deficient phenotype and the consequent accumulation of DNA damage sensitizes PDAC cells to PARPi. Combinations of BET inhibitors with PARPi may provide a novel strategy for treating PDAC. Fund NIH grants R01CA208272 and R21CA205501; UAB CMB T32 predoctoral training grant.

PARP inhibitor Olaparib increases the sensitization to radiotherapy in FaDu cells

“…In HR‐deficient head and neck cancers, Olaparib enhanced the radiotherapeutic ratio via disabling DNA replication processes . Moreover, recent studies have been focused on the combination of Olaparib with chemotherapeutic agents in cancer treatment . These combinations offer the prospect to broaden the clinical benefit of Olaparib beyond its use as monotherapy.…”

“…31 Moreover, recent studies have been focused on the combination of Olaparib with chemotherapeutic agents in cancer treatment. 32,33 These combinations offer the prospect to broaden the clinical benefit of Olaparib beyond its use as monotherapy. Although we have demonstrated the radiosensitization by Olaparib in radioresistant FaDu cells, the comprehensive mechanism remains a challengeable topic for future research.…”

IKBKE is a critical mediator of TAM-induced breast cancer resistance to BET inhibition

“…Recent data in pre-clinical studies revealed that BET inhibitors exert potential anti-tumor effects in non-small cell lung cancer cells [27], mixed-lineage leukemia gene-fused leukemia [28], and other solid tumors including pancreatic ductal adenocarcinoma [29], prostate cancer [30]. In several subtypes of breast cancer, BET inhibitors have been shown to display a strong anti-tumor effect.…”

Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

“…Targeting epigenetic factors such as BET family members cause defects in DSB repair and might provide beneficial effects in combination with PARP inhibitors [98]. Preclinical studies using BET inhibitor and PARP inhibitor combination have shown the superior anti-tumor efficacy compared to either agent alone in various cancer types [99][100][101]. We speculate that BET inhibition might enhance the anti-tumor activity of PARP inhibitor in SCLC through interference with DNA damage response.…”