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@ARTICLE{Lin:284396,
      author       = {X. Lin and A. Soni and R. Hessenow and M. Stuschke$^*$ and
                      G. Iliakis},
      title        = {{R}obust {R}adiosensitization by {C}ombined {T}reatment of
                      {C}ancer {C}ells with {T}alazoparib and {P}olθ
                      {I}nhibitors.},
      journal      = {International journal of radiation oncology, biology,
                      physics},
      volume       = {117},
      number       = {2S},
      issn         = {0360-3016},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DKFZ-2023-01985},
      pages        = {e245},
      year         = {2023},
      abstract     = {The PARP inhibitor talazoparib is synthetically lethal with
                      HR-defective tumors and functions as a potent
                      radiosensitizer specifically of cancer cells. Talazoparib
                      exerts this unique radiosensitizing property by shifting
                      ionizing radiation (IR)-induced DNA double strand break
                      (DSB) repair towards error-prone alternative end-joining
                      (alt-EJ). DNA polymerase theta (Polθ, encoded by POLQ) is a
                      key component of alt-EJ. Here, we tested the hypothesis that
                      inhibition of alt-EJ with Polθ ablation or using specific
                      small molecule inhibitors can further increase
                      talazoparib-induced radiosensitization.U2OS, A549, and their
                      corresponding POLQ ablated/mutant cell lines were treated
                      with talazoparib and/or Polθ inhibitors ART558/novobiocin
                      prior to irradiation. siRNAs against CtIP, MRE11, EXO1; and
                      a specific inhibitor of DNA2 were employed to suppress DNA
                      end resection. Radiosensitization was assessed by clonogenic
                      survival. Olaparib, rucaparib, and veliparib were also
                      tested under similar conditions. DSB repair and end
                      resection were measured by scoring γH2AX and RPA nuclear
                      foci, respectively. Chromosomal abnormalities were assessed
                      using G2-specific cytogenetics analysis.Genetic ablation or
                      pharmacological inhibition of Polθ robustly enhanced
                      talazoparib mediated radiosensitization by $∼40-70\%.$
                      Notably, Polθ inhibition had a much lower effect (by
                      $∼7-17\%)$ when combined with other clinically used PARP
                      inhibitors, olaparib, rucaparib, and veliparib. Polθ
                      inhibition significantly suppressed talazoparib-induced
                      translocation formation in irradiated cells. In addition,
                      combined treatment with Polθ inhibitor and talazoparib
                      attenuated DSB repair, resulting in $∼60\%$ unresolved
                      γH2AX foci and $∼40\%$ unresolved chromatid breaks at 5h
                      post IR. Talazoparib promoted resection of DNA ends as
                      demonstrated by an increase in RPA foci. The resection
                      process requires the activities of CtIP and MRE11, but not
                      of DNA2 or EXO1. Finally, CtIP and MRE11 knockdown impaired
                      radiosensitization following a combined talazoparib/Polθ
                      inhibition treatment.Talazoparib increases the reliance of
                      irradiated cancer cells on Polθ-mediated alt-EJ owing to
                      the increased CtIP/MRE11-dependent resection it produces.
                      Combining talazoparib with Polθ inhibitors has therefore
                      great potential in improving radiotherapy of human tumors.},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37784961},
      doi          = {10.1016/j.ijrobp.2023.06.1179},
      url          = {https://inrepo02.dkfz.de/record/284396},
}