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

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          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.

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          Most cited references23

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          BET inhibitors: a novel epigenetic approach

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            Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.

            One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide x 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.
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              Repression of BET activity sensitizes homologous recombination–proficient cancers to PARP inhibition

              Strategies to enhance response to poly(adenosine diphosphate–ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)–proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells. We also found that inhibition or depletion of BET proteins impairs transcription of BRCA1 and RAD51 , two genes essential for HR. Moreover, BETi treatment sensitized tumors to PARP inhibition in preclinical animal models of HR-proficient breast and ovarian cancers. Finally, we showed that the BRD4 gene was focally amplified across 20 types of common cancers. Combination with BETi could greatly expand the utility of PARP inhibition to patients with HR-proficient cancer.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                22 May 2019
                June 2019
                22 May 2019
                : 44
                : 419-430
                Affiliations
                [a ]Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL, USA
                [b ]Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, NP3551 North Pavilion UAB Hospital, Birmingham, AL, USA
                [c ]The Birmingham Veterans Administration Medical Center, 700 19 th St S, Birmingham, AL, USA
                [d ]Department of Radiation Oncology, University of Alabama at Birmingham, Hazelrig Salter Radiation Oncology Center, 1700 6 th Avenue S, Birmingham, AL, USA
                [e ]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
                Author notes
                [* ]Corresponding author at: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, VH 241, 1670 University Blvd, Birmingham, AL 35294, USA. kyoon@ 123456uab.edu
                [1]

                Current address: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.

                Article
                S2352-3964(19)30343-3
                10.1016/j.ebiom.2019.05.035
                6604668
                31126889
                00e630b1-e2e2-4a94-865e-9c8a1bada1c6
                © 2019 The Authors. Published by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 11 April 2019
                : 14 May 2019
                : 14 May 2019
                Categories
                Research paper

                bet bromodomain inhibitor (beti),pancreatic cancer,parp inhibitor (parpi),dna repair and damage,patient-derived xenograft model,dna double-strand break repair proteins

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