Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia Pub Date : 2025-03-16 DOI:10.1016/j.neo.2025.101152

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

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引用次数: 0

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.

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靶向BARD1抑制myc依赖性转录程序和胰腺导管腺癌的肿瘤生长

胰腺导管腺癌（PDAC）仍然是最致命的癌症之一，需要更好和更有效的治疗方法。BARD1或BRCA1-Associated -Ring Domain-1在同源重组修复（homologous recombination repair， HRR）中起关键作用。然而，其在PDAC中的功能和潜在的分子机制仍未完全阐明。在这里，我们证明BARD1在PDAC中过表达，其遗传抑制抑制c-Myc并破坏c-Myc依赖的转录程序。机制上，BARD1通过调控FBXW7，通过泛素-蛋白酶体系统稳定c-Myc。重要的是，使用sirna或CRISPR/Cas9缺失靶向BARD1可阻断PDAC体外和体内生长，对小鼠没有任何毒性迹象。利用477种DNA损伤反应化合物的重点药物文库，我们还发现BARD1抑制可增强几种临床相关药物的治疗效果（倍数变化≥4），包括PARPi，在HRR精通的PDAC细胞中。这些数据揭示了BARD1对于HRR熟练的PDAC是一个有吸引力的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.