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@ARTICLE{Sigaud:302166,
      author       = {R. Sigaud$^*$ and A. Stefanski and F. Selt$^*$ and D.
                      Kocher$^*$ and D. Usta$^*$ and D. J. Picard$^*$ and I.
                      Büdenbender$^*$ and M. Remke$^*$ and S. Pfister$^*$ and D.
                      Jones$^*$ and T. Brummer$^*$ and O. Witt$^*$ and T.
                      Milde$^*$},
      title        = {{M}ulti-omics dissection of {MAPK}-driven senescence
                      unveils therapeutic vulnerabilities in
                      {KIAA}1549::{BRAF}-fusion pediatric low-grade glioma
                      models.},
      journal      = {Signal transduction and targeted therapy},
      volume       = {10},
      number       = {1},
      issn         = {2095-9907},
      address      = {London},
      publisher    = {Macmillan Publishers, part of Springer Nature},
      reportid     = {DKFZ-2025-01284},
      pages        = {197},
      year         = {2025},
      note         = {#EA:B310#LA:B310#},
      abstract     = {Pilocytic astrocytomas (PA), the most common pediatric
                      low-grade gliomas (pLGGs), are characterized by genetic MAPK
                      pathway alterations leading to constitutive activation and
                      oncogene-induced senescence (OIS) accompanied with the
                      senescence-associated secretory phenotype (SASP). This study
                      investigates the molecular mechanisms of signaling pathways
                      regulating OIS and SASP in pLGGs using a multi-omics
                      approach. We utilized senescent DKFZ-BT66 cells derived from
                      a primary KIAA1549::BRAF-fusion positive PA to generate
                      RNA-sequencing and phospho-/proteomic datasets before and
                      after treatment with the MEK inhibitor trametinib.
                      Multi-omics factor analysis (MEFISTO) and single sample gene
                      set enrichment analysis (ssGSEA) were employed to identify
                      key OIS effectors and differentially regulated pathways upon
                      MAPK inhibition. Trametinib treatment inhibited MAPK
                      activity, OIS and SASP signatures across all omics levels,
                      functionally underscored by reduced sensitivity towards
                      senolytic drugs. We constructed a pathway network using a
                      prior knowledge approach, mapping n = 106 upregulated and n
                      = 84 downregulated direct downstream effectors of MAPK
                      leading to OIS/SASP. These effectors are associated with
                      better progression-free survival in pLGG patients,
                      independent of tumor site, level of resection, and genetic
                      aberration. Several compounds targeting signaling nodes
                      (SOD-1, IRS1, CDK1/2, CK2) involved in OIS and under MAPK
                      control were identified, of which n = 4 were validated in an
                      additional primary KIAA1549::BRAF fusion pLGG model as
                      potential new therapeutic vulnerabilities for the treatment
                      of pLGG. Our unbiased multi-omics signaling pathway analysis
                      identifies a specific and comprehensive network of
                      MAPK-OIS-SASP interdependencies in pLGGs and suggests new
                      therapeutic strategies for these tumors.},
      keywords     = {Humans / Pyrimidinones: pharmacology / Child / Glioma:
                      genetics / Glioma: drug therapy / Glioma: pathology /
                      Cellular Senescence: genetics / Cellular Senescence: drug
                      effects / Cell Line, Tumor / Oncogene Proteins, Fusion:
                      genetics / Pyridones: pharmacology / MAP Kinase Signaling
                      System: drug effects / MAP Kinase Signaling System: genetics
                      / Proto-Oncogene Proteins B-raf: genetics / Brain Neoplasms:
                      genetics / Brain Neoplasms: drug therapy / Brain Neoplasms:
                      pathology / Female / Gene Expression Regulation, Neoplastic:
                      drug effects / Male / Proteomics / Astrocytoma: genetics /
                      Astrocytoma: drug therapy / Astrocytoma: pathology /
                      Multiomics / Pyrimidinones (NLM Chemicals) / trametinib (NLM
                      Chemicals) / Oncogene Proteins, Fusion (NLM Chemicals) /
                      Pyridones (NLM Chemicals) / BRAF-KIAA1549 fusion protein,
                      human (NLM Chemicals) / Proto-Oncogene Proteins B-raf (NLM
                      Chemicals) / BRAF protein, human (NLM Chemicals)},
      cin          = {B310 / ED01 / HD01 / B360 / FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)B310-20160331 / I:(DE-He78)ED01-20160331 /
                      I:(DE-He78)HD01-20160331 / I:(DE-He78)B360-20160331 /
                      I:(DE-He78)FR01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40550805},
      doi          = {10.1038/s41392-025-02279-8},
      url          = {https://inrepo02.dkfz.de/record/302166},
}