CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma

IF 9.1 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-09-24 DOI:10.1073/pnas.2519568122

Wu Yang, Siying Wang, Shuyi Ji, Jian Wang, Shuo Lian, Zhe Li, Robin A. Jansen, Wei Wu, Kongyan Niu, Zhen Sun, Qi Jia, Jiaojiao Zheng, Huijue Zhu, Xuan Deng, Liqin Wang, Zhoulong Fan, Yaoping Shi, Cor Lieftink, Ming Guan, Roderick L. Beijersbergen, Wenxin Qin, Qiang Gao, René Bernards, Haojie Jin

{"title":"CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma","authors":"Wu Yang, Siying Wang, Shuyi Ji, Jian Wang, Shuo Lian, Zhe Li, Robin A. Jansen, Wei Wu, Kongyan Niu, Zhen Sun, Qi Jia, Jiaojiao Zheng, Huijue Zhu, Xuan Deng, Liqin Wang, Zhoulong Fan, Yaoping Shi, Cor Lieftink, Ming Guan, Roderick L. Beijersbergen, Wenxin Qin, Qiang Gao, René Bernards, Haojie Jin","doi":"10.1073/pnas.2519568122","DOIUrl":null,"url":null,"abstract":"Cholangiocarcinoma (CCA) remains a lethal malignancy with limited therapeutic options. Through genome-wide CRISPR-Cas9 screening, we identified the adenosine triphosphatase (ATPase) valosin-containing protein (VCP) as a critical dependency in CCA. Compound screens revealed that the VCP inhibitor CB-5339 potently suppresses CCA proliferation in a panel of patient-derived organoids by inducing cellular senescence. It is known that senescent cells persist, and this can contribute to therapy resistance. To address this, we combined CB-5339 with senolytic agents (ABT-263 and conatumumab), which selectively eliminate senescent CCA cells, resulting in enhanced tumor suppression both in vitro and in vivo. Clinical analysis showed that VCP overexpression in CCA patients correlates with poor prognosis. Our study unveils a “one-two punch” strategy, targeting VCP-mediated senescence followed by senolytic clearance, offering a promising therapeutic approach for CCA.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"38 1","pages":""},"PeriodicalIF":9.1000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Proceedings of the National Academy of Sciences of the United States of America","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1073/pnas.2519568122","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Cholangiocarcinoma (CCA) remains a lethal malignancy with limited therapeutic options. Through genome-wide CRISPR-Cas9 screening, we identified the adenosine triphosphatase (ATPase) valosin-containing protein (VCP) as a critical dependency in CCA. Compound screens revealed that the VCP inhibitor CB-5339 potently suppresses CCA proliferation in a panel of patient-derived organoids by inducing cellular senescence. It is known that senescent cells persist, and this can contribute to therapy resistance. To address this, we combined CB-5339 with senolytic agents (ABT-263 and conatumumab), which selectively eliminate senescent CCA cells, resulting in enhanced tumor suppression both in vitro and in vivo. Clinical analysis showed that VCP overexpression in CCA patients correlates with poor prognosis. Our study unveils a “one-two punch” strategy, targeting VCP-mediated senescence followed by senolytic clearance, offering a promising therapeutic approach for CCA.

查看原文本刊更多论文

CRISPR筛选确定atp酶VCP作为胆管癌的药物治疗易感性

胆管癌（CCA）仍然是一种致命的恶性肿瘤，治疗选择有限。通过全基因组CRISPR-Cas9筛选，我们确定了腺苷三磷酸酶（ATPase）含valosin蛋白（VCP）是CCA的关键依赖蛋白。复合筛选显示，VCP抑制剂CB-5339通过诱导细胞衰老，在一组患者来源的类器官中有效抑制CCA增殖。众所周知，衰老细胞持续存在，这可能有助于治疗抵抗。为了解决这个问题，我们将CB-5339与抗衰老药物（ABT-263和conatumumab）联合使用，选择性地消除衰老的CCA细胞，从而在体外和体内增强肿瘤抑制。临床分析显示，CCA患者VCP过表达与预后不良相关。我们的研究揭示了一种“组合拳”策略，针对vcp介导的衰老，随后是衰老清除，为CCA提供了一种有希望的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.