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@ARTICLE{Selt:181244,
      author       = {F. Selt$^*$ and R. Sigaud$^*$ and G. Valinciute$^*$ and P.
                      Sievers$^*$ and J. Zaman$^*$ and C. Alco and S. Schmid$^*$
                      and H. Peterziel$^*$ and J. W. Tsai and R. Guiho and J. P.
                      Martínez-Barbera and S. Pusch$^*$ and J. Deng and Y. Zhai
                      and C. M. van Tilburg$^*$ and M. U. Schuhman and A. E. L.
                      Damaty and P. Bandopadhayay and C. Herold-Mende and A. von
                      Deimling$^*$ and S. Pfister$^*$ and J. Montero and D.
                      Capper$^*$ and I. Oehme$^*$ and F. Sahm$^*$ and D. Jones$^*$
                      and O. Witt$^*$ and T. Milde$^*$},
      title        = {{BH}3 mimetics targeting {BCL}-{XL} impact the senescent
                      compartment of pilocytic astrocytoma.},
      journal      = {Neuro-Oncology},
      volume       = {25},
      number       = {4},
      issn         = {1522-8517},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2022-01890},
      pages        = {735-747},
      year         = {2023},
      note         = {#EA:B310#LA:B310# / 2023 Apr 6;25(4):735-747},
      abstract     = {Pilocytic astrocytoma (PA) is the most common pediatric
                      brain tumor and a mitogen-activated protein kinase
                      (MAPK)-driven disease. Oncogenic MAPK-signaling drives the
                      majority of cells into oncogene-induced senescence (OIS).
                      While OIS induces resistance to anti-proliferative
                      therapies, it represents a potential vulnerability
                      exploitable by senolytic agents.We established new
                      patient-derived PA cell lines that preserve molecular
                      features of the primary tumors and can be studied in OIS and
                      proliferation depending on expression ore repression of the
                      SV40 large T antigen. We determined expression of
                      anti-apoptotic BCL-2 members in these models and primary PA.
                      Dependence of senescent PA cells on anti-apoptotic BCL-2
                      members was investigated using a comprehensive set of
                      BH3-mimetics.Senescent PA cells upregulate BCL-XL upon
                      senescence induction and show dependency on BCL-XL for
                      survival. BH3 mimetics with high affinity for BCL-XL
                      (BCL-XLi) reduce metabolic activity and induce mitochondrial
                      apoptosis in senescent PA cells at nano-molar
                      concentrations. In contrast, BH3 mimetics without BCL-XLi
                      activity, conventional chemotherapy and MEK inhibitors show
                      no effect.Our data demonstrates that BCL-XL is critical for
                      survival of senescent PA tumor cells and provides
                      proof-of-principle for the use of clinically available
                      BCL-XL-dependent senolytics.},
      keywords     = {BCL-XL (Other) / BH3 mimetics (Other) / oncogene-induced
                      senescence (Other) / pilocytic astrocytoma (Other)},
      cin          = {B310 / HD01 / B300 / BE01 / B062 / B360},
      ddc          = {610},
      cid          = {I:(DE-He78)B310-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B300-20160331 / I:(DE-He78)BE01-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)B360-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35977048},
      doi          = {10.1093/neuonc/noac199},
      url          = {https://inrepo02.dkfz.de/record/181244},
}