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@ARTICLE{Heinst:292539,
      author       = {L. Heinst and K. Lee$^*$ and R. Berthold and I. Isfort and
                      S. Wosnig and A. Kuntze and S. Hafner and B. Altvater and C.
                      Rössig and P. Åman and E. Wardelmann and C. Scholl$^*$ and
                      W. Hartmann and S. Fröhling$^*$ and M. Trautmann},
      title        = {{E}xploiting {WEE}1 kinase activity as
                      {FUS}::{DDIT}3-dependent therapeutic vulnerability in myxoid
                      liposarcoma.},
      journal      = {Clinical cancer research},
      volume       = {30},
      number       = {21},
      issn         = {1078-0432},
      address      = {Philadelphia, Pa. [u.a.]},
      publisher    = {AACR},
      reportid     = {DKFZ-2024-01782},
      pages        = {4974-4986},
      year         = {2024},
      note         = {2024 Nov 1;30(21):4974-4986},
      abstract     = {The pathognomonic FUS::DDIT3 fusion protein drives myxoid
                      liposarcoma (MLS) tumorigenesis via aberrant transcriptional
                      activation of oncogenic signaling. Since FUS::DDIT3 has so
                      far not been pharmacologically tractable to selectively
                      target MLS cells, this study investigated the functional
                      role of the cell cycle regulator WEE1 as novel
                      FUS::DDIT3‑dependent therapeutic vulnerability in
                      MLS.Immunohistochemical evaluation of the cell cycle
                      regulator WEE1 was performed in a large cohort of MLS
                      specimens. FUS::DDIT3 dependency and biological function of
                      the G1/S cell cycle checkpoint were analyzed in a
                      mesenchymal stem cell model and liposarcoma cell lines in
                      vitro. WEE1 activity was modulated by RNAi‑mediated
                      knockdown and the small molecule inhibitor MK-1775
                      (Adavosertib). An established MLS cell line-based chicken
                      chorioallantoic membrane model was employed for in vivo
                      confirmation.We demonstrate that enhanced WEE1 pathway
                      activity represents a hallmark of FUS::DDIT3‑expressing
                      cell lines as well as MLS tissue specimens and that WEE1 is
                      required for MLS cellular survival in vitro and in vivo.
                      Pharmacologic inhibition of WEE1 activity results in DNA
                      damage accumulation and cell cycle progression forcing cells
                      to undergo apoptotic cell death. In addition, our results
                      uncover FUS::DDIT3-dependent WEE1 expression as an oncogenic
                      survival mechanism to tolerate high proliferation and
                      resulting replication stress in MLS. Fusion protein-driven
                      G1/S cell cycle checkpoint deregulation via overactive
                      Cyclin E/CDK2 complexes thereby contributes to enhanced WEE1
                      inhibitor sensitivity in MLS.Our preclinical study
                      identifies WEE1-mediated replication stress tolerance as
                      molecular vulnerability in FUS::DDIT3-driven MLS
                      tumorigenesis that could represent a novel target for
                      therapeutic intervention.},
      cin          = {B340 / HD01 / B290},
      ddc          = {610},
      cid          = {I:(DE-He78)B340-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B290-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39207225},
      doi          = {10.1158/1078-0432.CCR-24-1152},
      url          = {https://inrepo02.dkfz.de/record/292539},
}