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Article

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

1
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
2
Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
3
The Birmingham Veterans Administration Medical Center, Birmingham, AL 35233, USA
4
Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35205, USA
5
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
6
O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Alessio Giuseppe Morganti
Cancers 2021, 13(14), 3470; https://doi.org/10.3390/cancers13143470
Received: 14 June 2021 / Revised: 2 July 2021 / Accepted: 7 July 2021 / Published: 11 July 2021
(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)
The BET bromodomain inhibitor JQ1 slows tumor growth in preclinical models of pancreatic cancer. However, as a single agent, it does not induce tumor regressions. We hypothesized that JQ1 would sensitize pancreatic tumors to gemcitabine, a drug used for patients with this tumor type. We evaluated the efficacy of JQ1 + gemcitabine in pancreatic cancer cell lines and in two patient-derived xenograft models. The data show that JQ1 + gemcitabine is synergistic in vitro and that this combination has greater efficacy than either drug alone in vivo. RNA-seq analyses to identify mechanisms that may contribute to the observed synergy demonstrated that JQ1 + gemcitabine selectively inhibits expression of proteins necessary for cholesterol biosynthesis and lipid metabolism that support tumor cell proliferation. The data indicate that a BET inhibitor + gemcitabine warrants further investigation for the treatment 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 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 (P < 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. View Full-Text
Keywords: pancreatic ductal adenocarcinoma; gemcitabine; BET bromodomain inhibitor; JQ1; combination therapy; HMGCS2; APOC1; LXR/RXR; RNA-seq; patient-derived xenograft pancreatic ductal adenocarcinoma; gemcitabine; BET bromodomain inhibitor; JQ1; combination therapy; HMGCS2; APOC1; LXR/RXR; RNA-seq; patient-derived xenograft
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MDPI and ACS Style

Miller, A.L.; Garcia, P.L.; Fehling, S.C.; Gamblin, T.L.; Vance, R.B.; Council, L.N.; Chen, D.; Yang, E.S.; van Waardenburg, R.C.A.M.; Yoon, K.J. The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer. Cancers 2021, 13, 3470. https://doi.org/10.3390/cancers13143470

AMA Style

Miller AL, Garcia PL, Fehling SC, Gamblin TL, Vance RB, Council LN, Chen D, Yang ES, van Waardenburg RCAM, Yoon KJ. The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer. Cancers. 2021; 13(14):3470. https://doi.org/10.3390/cancers13143470

Chicago/Turabian Style

Miller, Aubrey L., Patrick L. Garcia, Samuel C. Fehling, Tracy L. Gamblin, Rebecca B. Vance, Leona N. Council, Dongquan Chen, Eddy S. Yang, Robert C.A.M. van Waardenburg, and Karina J. Yoon. 2021. "The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer" Cancers 13, no. 14: 3470. https://doi.org/10.3390/cancers13143470

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