CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Wu Yang
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Siying Wang
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Shuyi Ji
Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University
Jian Wang
Shuo Lian
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Zhe Li
Robin A. Jansen
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Wei Wu
Kongyan Niu
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Zhen Sun
Qi Jia
Jiaojiao Zheng
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Huijue Zhu
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Xuan Deng
Department of Laboratory Medicine, Huashan Hospital, Fudan University
Liqin Wang
State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center
Zhoulong Fan
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, Shanghai Key Laboratory for Antibody-Drug Conjugates with Innovative Target, State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences
Yaoping Shi
Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Cor Lieftink
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Ming Guan
Department of Laboratory Medicine, Huashan Hospital, Fudan University
Roderick L. Beijersbergen
Wenxin Qin
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Qiang Gao
René Bernards
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Haojie Jin
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital