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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/14/3470 |
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| author | Aubrey L. Miller 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 Karina J. Yoon |
| author_facet | Aubrey L. Miller 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 Karina J. Yoon |
| author_sort | Aubrey L. Miller |
| collection | DOAJ |
| description | 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 (<i>P</i> < 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. |
| first_indexed | 2024-03-10T09:44:12Z |
| format | Article |
| id | doaj.art-912681700fb549569bc2af601bbd08d0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:44:12Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-912681700fb549569bc2af601bbd08d02023-11-22T03:23:46ZengMDPI AGCancers2072-66942021-07-011314347010.3390/cancers13143470The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic CancerAubrey L. Miller0Patrick L. Garcia1Samuel C. Fehling2Tracy L. Gamblin3Rebecca B. Vance4Leona N. Council5Dongquan Chen6Eddy S. Yang7Robert C. A. M. van Waardenburg8Karina J. Yoon9Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35205, USADepartment of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USAGemcitabine 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 (<i>P</i> < 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.https://www.mdpi.com/2072-6694/13/14/3470pancreatic ductal adenocarcinomagemcitabineBET bromodomain inhibitorJQ1combination therapyHMGCS2 |
| spellingShingle | Aubrey L. Miller 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 Karina J. Yoon The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer Cancers pancreatic ductal adenocarcinoma gemcitabine BET bromodomain inhibitor JQ1 combination therapy HMGCS2 |
| title | The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer |
| title_full | The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer |
| title_fullStr | The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer |
| title_full_unstemmed | The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer |
| title_short | The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer |
| title_sort | bet inhibitor jq1 augments the antitumor efficacy of gemcitabine in preclinical models of pancreatic cancer |
| topic | pancreatic ductal adenocarcinoma gemcitabine BET bromodomain inhibitor JQ1 combination therapy HMGCS2 |
| url | https://www.mdpi.com/2072-6694/13/14/3470 |
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