CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma
Year: 2025
Type: article
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.
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
Institutions: Shanghai Jiao Tong University, Renji Hospital, The Netherlands Cancer Institute, Shanghai Cancer Institute, Oncode Institute, Tongji University, Fudan University, Zhongshan Hospital, Shanghai East Hospital, Huashan Hospital, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4414465436