The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer
In pancreatic cancer the tumor microenvironment (TME) can account for up to 90% of the tumor mass. The TME drives essential functions in disease progression, invasion and metastasis. Tumor cells can use epigenetic modulation to evade immune recognition and shape the TME toward an immunosuppressive p...
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MDPI AG
2020-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/1/96 |
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| author | Ana S. Leal Phillip Liu Teresa Krieger-Burke Bruce Ruggeri Karen T. Liby |
| author_facet | Ana S. Leal Phillip Liu Teresa Krieger-Burke Bruce Ruggeri Karen T. Liby |
| author_sort | Ana S. Leal |
| collection | DOAJ |
| description | In pancreatic cancer the tumor microenvironment (TME) can account for up to 90% of the tumor mass. The TME drives essential functions in disease progression, invasion and metastasis. Tumor cells can use epigenetic modulation to evade immune recognition and shape the TME toward an immunosuppressive phenotype. Bromodomain inhibitors are a class of drugs that target BET (bromodomain and extra-terminal) proteins, impairing their ability to bind to acetylated lysines and therefore interfering with transcriptional initiation and elongation. INCB057643 is a new generation, orally bioavailable BET inhibitor that was developed for treating patients with advanced malignancies. Kras<sup>G12D/+</sup>; Trp53<sup>R172H/+</sup>; Pdx-1-Cre (KPC) mice mimic human disease, with similar progression and incidence of metastasis. Treatment of established tumors in KPC mice with INCB057643 increased survival by an average of 55 days, compared to the control group. Moreover, INCB057643 reduced metastatic burden in these mice. KPC mice treated with INCB057643, starting at 4 weeks of age, showed beneficial changes in immune cell populations in the pancreas and liver. Similarly, INCB057643 modified immune cell populations in the pancreas of Kras<sup>G12D/+</sup>; Pdx-1-Cre (KC) mice with pancreatitis, an inflammatory process known to promote pancreatic cancer progression. The data presented here suggest that the bromodomain inhibitor INCB057643 modulates the TME, reducing disease burden in two mouse models of pancreatic cancer. Furthermore, this work suggests that BRD4 may play a role in establishing the TME in the liver, a primary metastatic site for pancreatic cancer. |
| first_indexed | 2024-03-10T13:39:13Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T13:39:13Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
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| series | Cancers |
| spelling | doaj.art-efbfa0d889bf4f65879d47d03ccf078c2023-11-21T03:13:02ZengMDPI AGCancers2072-66942020-12-011319610.3390/cancers13010096The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic CancerAna S. Leal0Phillip Liu1Teresa Krieger-Burke2Bruce Ruggeri3Karen T. Liby4Department of Pharmacology & Toxicology, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USAIncyte Corporation, Wilmington, DE 19803, USADepartment of Pharmacology & Toxicology, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USAIncyte Corporation, Wilmington, DE 19803, USADepartment of Pharmacology & Toxicology, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USAIn pancreatic cancer the tumor microenvironment (TME) can account for up to 90% of the tumor mass. The TME drives essential functions in disease progression, invasion and metastasis. Tumor cells can use epigenetic modulation to evade immune recognition and shape the TME toward an immunosuppressive phenotype. Bromodomain inhibitors are a class of drugs that target BET (bromodomain and extra-terminal) proteins, impairing their ability to bind to acetylated lysines and therefore interfering with transcriptional initiation and elongation. INCB057643 is a new generation, orally bioavailable BET inhibitor that was developed for treating patients with advanced malignancies. Kras<sup>G12D/+</sup>; Trp53<sup>R172H/+</sup>; Pdx-1-Cre (KPC) mice mimic human disease, with similar progression and incidence of metastasis. Treatment of established tumors in KPC mice with INCB057643 increased survival by an average of 55 days, compared to the control group. Moreover, INCB057643 reduced metastatic burden in these mice. KPC mice treated with INCB057643, starting at 4 weeks of age, showed beneficial changes in immune cell populations in the pancreas and liver. Similarly, INCB057643 modified immune cell populations in the pancreas of Kras<sup>G12D/+</sup>; Pdx-1-Cre (KC) mice with pancreatitis, an inflammatory process known to promote pancreatic cancer progression. The data presented here suggest that the bromodomain inhibitor INCB057643 modulates the TME, reducing disease burden in two mouse models of pancreatic cancer. Furthermore, this work suggests that BRD4 may play a role in establishing the TME in the liver, a primary metastatic site for pancreatic cancer.https://www.mdpi.com/2072-6694/13/1/96pancreatic cancerbromodomain inhibitorsinflammatory tumor microenvironment |
| spellingShingle | Ana S. Leal Phillip Liu Teresa Krieger-Burke Bruce Ruggeri Karen T. Liby The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer Cancers pancreatic cancer bromodomain inhibitors inflammatory tumor microenvironment |
| title | The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer |
| title_full | The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer |
| title_fullStr | The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer |
| title_full_unstemmed | The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer |
| title_short | The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer |
| title_sort | bromodomain inhibitor incb057643 targets both cancer cells and the tumor microenvironment in two preclinical models of pancreatic cancer |
| topic | pancreatic cancer bromodomain inhibitors inflammatory tumor microenvironment |
| url | https://www.mdpi.com/2072-6694/13/1/96 |
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