2. Academic Validation
  3. Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2

  • Gut. 2024 May 31:gutjnl-2023-331519. doi: 10.1136/gutjnl-2023-331519.
Markus Vogt 1 2,  Nevenka Dudvarski Stankovic 1 2,  Yiliam Cruz Garcia 1 2,  Julia Hofstetter 1,  Katharina Schneider 1 2 3,  Filiz Kuybu 3,  Theresa Hauck 3,  Bikash Adhikari 1 2,  Anton Hamann 4,  Yamila Rocca 5,  Lara Grysczyk 1,  Benedikt Martin 1,  Anneli Gebhardt-Wolf 6,  Armin Wiegering 6 7,  Markus Diefenbacher 8 9,  Georg Gasteiger 5,  Stefan Knapp 4,  Dieter Saur 10,  Martin Eilers 6,  Mathias Rosenfeldt 11,  Florian Erhard 12,  Seychelle M Vos 3,  Elmar Wolf 13 2
Affiliations

Affiliations

  • 1 Cancer Systems Biology Group, Chair of Biochemistry and Molecular Biology, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany.
  • 2 Institute of Biochemistry, University of Kiel, Kiel, Germany.
  • 3 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 4 Institute for Pharmaceutical Chemistry, Goethe-University Frankfurt, Frankfurt am Main, Germany.
  • 5 Max Planck Research Group and Institute of Systems Immunology, University of Würzburg, Würzburg, Germany.
  • 6 Chair of Biochemistry and Molecular Biology, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany.
  • 7 Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany.
  • 8 Comprehensive Pneumology Center (CPC)/Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL/CPC-M), Munich, Germany.
  • 9 Ludwig-Maximilian-Universität München (LMU), Munich, Germany.
  • 10 Institute of Translational Cancer Research, TUM School of Medicine and Health, Munich, Germany.
  • 11 Institute of Pathology, University of Würzburg, Würzburg, Germany.
  • 12 Computational Systems Virology and Bioinformatics, Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
  • 13 Cancer Systems Biology Group, Chair of Biochemistry and Molecular Biology, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany elmar.wolf@biochem.uni-kiel.de.
PMID: 38821858 DOI: 10.1136/gutjnl-2023-331519
Abstract

Objective: The hallmark oncogene MYC drives the progression of most tumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC).

Design: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumours in mice.

Results: Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immunoevasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven Cancer.

Conclusion: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.

Keywords

GENE REGULATION; GENE TARGETING; IMMUNOTHERAPY; ONCOGENES; PANCREATIC CANCER.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114429
    99.88%, RUVBL1/2抑制剂
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