2. Academic Validation
  3. CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma

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

  • Proc Natl Acad Sci U S A. 2025 Sep 30;122(39):e2519568122. doi: 10.1073/pnas.2519568122.
Wu Yang # 1 2,  Siying Wang # 1 2,  Shuyi Ji # 3 4,  Jian Wang # 1,  Shuo Lian 1,  Zhe Li 1,  Robin A Jansen 2,  Wei Wu 1,  Kongyan Niu 1,  Zhen Sun 1,  Qi Jia 1,  Jiaojiao Zheng 1,  Huijue Zhu 1,  Xuan Deng 5,  Liqin Wang 6,  Zhoulong Fan 7,  Yaoping Shi 8,  Cor Lieftink 2,  Ming Guan 5,  Roderick L Beijersbergen 2,  Wenxin Qin 1,  Qiang Gao 4,  René Bernards 1 2,  Haojie Jin 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
  • 2 Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066CX, The Netherlands.
  • 3 Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
  • 4 Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 5 Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 6 State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 7 National Key Laboratory of Innovative Immunotherapy, Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 8 Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • # Contributed equally.
PMID: 40991439 DOI: 10.1073/pnas.2519568122
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.

Keywords

CRISPR-Cas9 screening; VCP; cholangiocarcinoma; senescence.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12861
    99.90%, p97 AAA ATPase/VCP Inhibitor
    p97
  • HY-128724
    99.58%, p97 Inhibitor
    p97