2. Academic Validation
  3. Targeting Mutual Dependence of Phosphatidylinositol-3-Kinase α/δ and Small Ubiquitin-Like Modifier Signaling in Pancreatic Cancer

Targeting Mutual Dependence of Phosphatidylinositol-3-Kinase α/δ and Small Ubiquitin-Like Modifier Signaling in Pancreatic Cancer

  • Gastroenterology. 2025 Oct 27:S0016-5085(25)05903-7. doi: 10.1053/j.gastro.2025.08.018.
Hazal Köse 1,  Christian Schneeweis 2,  Philipp Putze 2,  Constanza Tapia Contreras 3,  Laura Ferreiro 1,  Leonie Witte 3,  Ilaria Deidda 3,  Frederik Herzberg 1,  Sophie Ebert 3,  Juraj Jakubik 4,  Leoni Moldaner 4,  Jovan Todorovic 5,  Isabelle Träger 1,  Chuanbing Zang 1,  Uta M Demel 1,  Elisabeth Hessmann 6,  Marieluise Kirchner 7,  Simone Rhein 8,  Jens Hoffmann 8,  Zuzana Tatarova 9,  Michael Ghadimi 3,  Dieter Saur 10,  Kai Kappert 11,  Philipp Mertins 7,  Günter Schneider 12,  Ulrich Keller 13,  Matthias Wirth 14
Affiliations

Affiliations

  • 1 Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
  • 2 Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, Munich, Germany.
  • 3 Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
  • 4 Institute for Tumor Biology and Experimental Therapy, German Center for Translational Cancer Research (DKTK), Partner Site Frankfurt/Mainz, Georg-Speyer-Haus, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 5 Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
  • 6 Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany; CCC-N (Comprehensive Cancer Center Lower Saxony), Göttingen, Germany; Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Germany.
  • 7 Max Delbrück Center for Molecular Medicine, Berlin, Germany; Core Unit Proteomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • 8 EPO, Experimental Pharmacology and Oncology Berlin-Buch GmbH, Berlin, Germany.
  • 9 Institute for Tumor Biology and Experimental Therapy, German Center for Translational Cancer Research (DKTK), Partner Site Frankfurt/Mainz, Georg-Speyer-Haus, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Frankfurt Cancer Institute, Frankfurt, Germany.
  • 10 Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, Munich, Germany; German Center for Translational Cancer Research (DKTK), Partner Site Munich, Munich, Germany.
  • 11 Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 12 Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, Munich, Germany; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany; CCC-N (Comprehensive Cancer Center Lower Saxony), Göttingen, Germany; Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Germany. Electronic address: guenter.schneider@med.uni-goettingen.de.
  • 13 Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Cluster of Excellence ImmunoPreCept, Berlin, Germany; German Center for Translational Cancer Research (DKTK), Partner Site Berlin, Berlin, Germany. Electronic address: ulrich.keller@charite.de.
  • 14 Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany; German Center for Translational Cancer Research (DKTK), Partner Site Berlin, Berlin, Germany. Electronic address: matthias.wirth@med.uni-goettingen.de.
PMID: 41143762 DOI: 10.1053/j.gastro.2025.08.018
Abstract

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal Cancer, with a 5-year survival rate of <13%. Despite advances in diagnostics and treatments, the standard of care for PDAC remains inadequate, and most patients develop resistance to therapy. Targeted approaches, such as Kirsten rat sarcoma (KRAS) inhibition, have shown promise in preclinical models, although clinical application remains challenged by the rapid development of resistance. The phosphatidylinositol-3-kinase (PI3K) signaling pathway is critical for PDAC development and maintenance, yet pharmacologic targeting has failed to yield significant clinical benefits.

Methods: To investigate the relationship between the PI3K and small ubiquitin-like modifier (SUMO) pathways in PDAC, we used a comprehensive approach that included unbiased genome-wide clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 resistance screens, pharmacologic screens, transcriptomics, proteomics, and phosphoproteomics experiments. Genetic knockout models were applied to validate our findings. A novel molecularly targeted combination therapy was tested in preclinical mouse models.

Results: Using genetic and pharmacologic screenings, we discovered a mutual and targetable codependence between the PI3K and the SUMO pathways. Simultaneous inhibition of PIK3α and PIK3δ, combined with SUMO-activating E1 targeting, triggered synthetic lethality and cell death. In syngeneic orthotopic immune-competent PDAC models, this combination therapy reduced tumor growth and promoted immune cell infiltration and activity.

Conclusions: Our study introduces a novel rational combination therapy in PDAC. Dual targeting of PI3Kα/δ and SUMO signaling bears potential for clinical translation.

Keywords

Combination Therapy; PI3K; Pancreatic Cancer; Regulated Cell Death; SUMOylation.

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