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@ARTICLE{Kse:305545,
      author       = {H. Köse and C. Schneeweis and P. Putze and C. T. Contreras
                      and L. Ferreiro and L. Witte and I. Deidda and F. Herzberg
                      and S. Ebert and J. Jakubik$^*$ and L. Moldaner$^*$ and J.
                      Todorovic and I. Träger and C. Zang and U. M. Demel and E.
                      Hessmann and M. Kirchner and S. Rhein and J. Hoffmann and Z.
                      Tatarova$^*$ and M. Ghadimi and D. Saur$^*$ and K. Kappert
                      and P. Mertins and G. Schneider and U. Keller and M.
                      Wirth$^*$},
      title        = {{T}argeting {M}utual {D}ependence of
                      {P}hosphatidylinositol-3-{K}inase α/δ and {S}mall
                      {U}biquitin-{L}ike {M}odifier {S}ignaling in {P}ancreatic
                      {C}ancer.},
      journal      = {Gastroenterology},
      volume       = {nn},
      issn         = {0016-5085},
      address      = {New York, NY},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-02219},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {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.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.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.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 (Other) / PI3K (Other) / Pancreatic
                      Cancer (Other) / Regulated Cell Death (Other) / SUMOylation
                      (Other)},
      cin          = {FM01 / MU01 / BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)FM01-20160331 / I:(DE-He78)MU01-20160331 /
                      I:(DE-He78)BE01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41143762},
      doi          = {10.1053/j.gastro.2025.08.018},
      url          = {https://inrepo02.dkfz.de/record/305545},
}