2. Academic Validation
  3. Epigenetic drug screening defines a PRMT5 inhibitor-sensitive pancreatic cancer subtype

Epigenetic drug screening defines a PRMT5 inhibitor-sensitive pancreatic cancer subtype

  • JCI Insight. 2022 May 23;7(10):e151353. doi: 10.1172/jci.insight.151353.
Felix Orben 1,  Katharina Lankes 1,  Christian Schneeweis 1 2,  Zonera Hassan 1,  Hannah Jakubowsky 2,  Lukas Krauß 1 3,  Fabio Boniolo 2,  Carolin Schneider 1 3,  Arlett Schäfer 1,  Janine Murr 1,  Christoph Schlag 1,  Bo Kong 4 5,  Rupert Öllinger 6,  Chengdong Wang 7 8 9,  Georg Beyer 10 11,  Ujjwal M Mahajan 10 11,  Yonggan Xue 10 11,  Julia Mayerle 10 11 12,  Roland M Schmid 1 11,  Bernhard Kuster 7 12 13,  Roland Rad 6 12,  Christian J Braun 14,  Matthias Wirth 15,  Maximilian Reichert 1 11 12 16 17,  Dieter Saur 2 12,  Günter Schneider 1 3
Affiliations

Affiliations

  • 1 Medical Clinic and Polyclinic II, Klinikum rechts der Isar and.
  • 2 Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich (TUM), Munich, Germany.
  • 3 University Medical Center Göttingen, Department of General, Visceral and Pediatric Surgery, Göttingen, Germany.
  • 4 Department of Surgery, Klinikum rechts der Isar, TUM, Munich, Germany.
  • 5 Department of General Surgery, University of Ulm, Ulm, Germany.
  • 6 Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine and.
  • 7 Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, TUM, Freising, Germany.
  • 8 Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
  • 9 Department of Surgery, Children's Hospital of Soochow University, Suzhou, China.
  • 10 Department of Medicine II, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU Munich), Munich, Germany.
  • 11 Bavarian Cancer Research Center (BZKF), Munich, Germany.
  • 12 German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 13 Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), TUM, Freising, Germany.
  • 14 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
  • 15 Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • 16 Center for Protein Assemblies (CPA), TUM, Garching, Germany.
  • 17 Translational Pancreatic Research Cancer Center, Medical Clinic and Polyclinic II, Klinikum rechts der Isar, TUM, Munich, Germany.
PMID: 35439169 DOI: 10.1172/jci.insight.151353
Abstract

Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor for tumor subtypes with activating aberrations in the MYC pathway, creating an urgent need for novel therapeutic targets. To unbiasedly find MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic Cancer cell lines. Here, we found that protein arginine N-methyltransferase 5 (PRMT5) inhibitors triggered an MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. By the use of gain- and loss-of-function models, we confirmed the increased efficacy of PRMT5 inhibitors in MYC-deregulated PDACs. Although inhibition of PRMT5 was inducing DNA damage and arresting PDAC cells in the G2/M phase of the cell cycle, apoptotic cell death was executed predominantly in cells with high MYC expression. Experiments in primary patient-derived PDAC models demonstrated the existence of a highly PRMT5 inhibitor-sensitive subtype. Our work suggests developing PRMT5 inhibitor-based therapies for PDAC.

Keywords

Cancer; Cell Biology; Oncology; Pharmacology.

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