The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer

Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cel...

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Bibliographic Details
Published in:Cancers 2021-07, Vol.13 (14), p.3470
Main Authors: Miller, Aubrey L, Garcia, Patrick L, Fehling, Samuel C, Gamblin, Tracy L, Vance, Rebecca B, Council, Leona N, Chen, Dongquan, Yang, Eddy S, van Waardenburg, Robert C A M, Yoon, Karina J
Format: Article
Language:English
Subjects:
Antitumor activity
Apoptosis
Biosynthesis
Cancer therapies
Caspase-3
Cell cycle
Cell proliferation
Cholesterol
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Gemcitabine
Gene expression
Genomics
Kinases
Lipid metabolism
Pancreatic cancer
Patients
Retinoid X receptors
Software
Tumor cell lines
Tumors
Variance analysis
Xenografts
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Summary:Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models ( < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13143470