Document Type
Article
Publication Date
5-1-2025
Abstract
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.
Recommended Citation
Patel, Sohum; Jenkins, Eleanor; Kusurkar, Rutuj P.; Lee, Sherry; Jiang, Wei; Nevler, Avinoam; McCoy, Matthew; Pishvaian, Michael J.; Sears, Rosalie C.; Brody, Jonathan R.; Yeo, Charles J.; and Jain, Aditi, "Targeting BARD1 Suppresses a Myc-Dependent Transcriptional Program and Tumor Growth in Pancreatic Ductal Adenocarcinoma" (2025). Department of Surgery Faculty Papers. Paper 283.
https://jdc.jefferson.edu/surgeryfp/283
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
40096771
Language
English
Included in
Amino Acids, Peptides, and Proteins Commons, Cancer Biology Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Neoplasms Commons, Pathology Commons, Surgery Commons
Comments
This article is the author's final published version in Neoplasia (United States), Volume 63, 2025, Article number 101152.
The published version is available at https://doi.org/10.1016/j.neo.2025.101152.
Copyright © 2025 The Authors