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.
| Original language | English |
|---|---|
| Pages (from-to) | 419-430 |
| Number of pages | 12 |
| Journal | EBioMedicine |
| Volume | 44 |
| DOIs | |
| State | Published - Jun 2019 |
Bibliographical note
Funding Information:K.J.Y receives grants from the National Institutes of Health (R01CA208272 and R21CA205501). A.L.M. received the predoctoral training fellowship in CMB T32 training grant (2017–2018). R.C.A.M.vW received DoD OCRP pilot grant (W81XWH-15-1-0198). E.S.Y. receives personal fee from AstraZeneca and receives funding from ASCO, Eli Lilly, Novartis, and PUMA. J.E.B is now an executive and shareholder of Novartis AG, and has been a founder and shareholder of SHAPE (acquired by Medivir), Acetylon (acquired by Celgene), Tensha (acquired by Roche), Syros, Regency and C4 Therapeutics. J.E.B. has a patent US 8,981,083 B2 to Roche-Genetech. All other authors declare no conflicts of interest.
Funding Information:
This study was supported by the National Institutes of Health (National Cancer Institute) grants R01CA208272 and R21CA205501 (K.J.Y.). A.L.M. is a recipient of the predoctoral training fellowship in Cell and Molecular Biology (CMB) T32 training grant (2017?2018). R.C.A.M.vW. is supported by DoD OCRP pilot grant W81XWH-15-1-0198. E.S?Y is supported by AstraZeneca, ASCO, Eli Lilly, Novartis and PUMA. The funding sources had no role in the study design, data collection, analysis and interpretation, and writing of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Publisher Copyright:
© 2019
Keywords
- BET bromodomain inhibitor (BETi)
- DNA double-strand break repair proteins
- DNA repair and damage
- PARP inhibitor (PARPi)
- Pancreatic cancer
- Patient-derived xenograft model
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)
