Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC ar...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000314 |
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| author | Sohum Patel Eleanor Jenkins Rutuj P Kusurkar Sherry Lee Wei Jiang Avinoam Nevler Matthew McCoy Michael J Pishvaian Rosalie C Sears Jonathan R Brody Charles J Yeo Aditi Jain |
| author_facet | Sohum Patel Eleanor Jenkins Rutuj P Kusurkar Sherry Lee Wei Jiang Avinoam Nevler Matthew McCoy Michael J Pishvaian Rosalie C Sears Jonathan R Brody Charles J Yeo Aditi Jain |
| author_sort | Sohum Patel |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin–proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth in vitro and in vivo, without any signs of toxicity to mice. Using a focused drug library of 477 DNA damage response compounds, we also found that BARD1 inhibition enhances therapeutic efficacy of several clinically relevant agents (fold changes ≥4), including PARPi, in HRR proficient PDAC cells. These data uncover BARD1 as an attractive therapeutic target for HRR proficient PDAC. |
| format | Article |
| id | doaj-art-4a55323f3ec84de18595fbf62d5198d1 |
| institution | OA Journals |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-4a55323f3ec84de18595fbf62d5198d12025-08-20T01:55:34ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-05-016310115210.1016/j.neo.2025.101152Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinomaSohum Patel0Eleanor Jenkins1Rutuj P Kusurkar2Sherry Lee3Wei Jiang4Avinoam Nevler5Matthew McCoy6Michael J Pishvaian7Rosalie C Sears8Jonathan R Brody9Charles J Yeo10Aditi Jain11Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USADepartment of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USADepartment of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USADepartment of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USAInnovation Center for Biomedical Informatics & Lombardi Comprehensive Cancer Center, Washington, DC, USADepartment of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USADepartment of Molecular and Medical Genetics, and Brenden-Colson Center for Pancreatic Care Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USADepartment of Surgery, and Brenden-Colson Center for Pancreatic Care Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USADepartment of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USADepartment of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; Corresponding author at: Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, 1015 Walnut Street, Curtis Building, Room 618, Philadelphia, PA 19107 USA.Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin–proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth in vitro and in vivo, without any signs of toxicity to mice. Using a focused drug library of 477 DNA damage response compounds, we also found that BARD1 inhibition enhances therapeutic efficacy of several clinically relevant agents (fold changes ≥4), including PARPi, in HRR proficient PDAC cells. These data uncover BARD1 as an attractive therapeutic target for HRR proficient PDAC.http://www.sciencedirect.com/science/article/pii/S1476558625000314Pancreatic ductal adenocarcinomaBARD1PARP inhibitorDNA damagec-Myc |
| spellingShingle | Sohum Patel Eleanor Jenkins Rutuj P Kusurkar Sherry Lee Wei Jiang Avinoam Nevler Matthew McCoy Michael J Pishvaian Rosalie C Sears Jonathan R Brody Charles J Yeo Aditi Jain Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma Neoplasia: An International Journal for Oncology Research Pancreatic ductal adenocarcinoma BARD1 PARP inhibitor DNA damage c-Myc |
| title | Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma |
| title_full | Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma |
| title_fullStr | Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma |
| title_full_unstemmed | Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma |
| title_short | Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma |
| title_sort | targeting bard1 suppresses a myc dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma |
| topic | Pancreatic ductal adenocarcinoma BARD1 PARP inhibitor DNA damage c-Myc |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000314 |
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