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@ARTICLE{Varol:301485,
      author       = {A. Varol and S. M. Klauck$^*$ and S. P. Lees-Miller and T.
                      Efferth},
      title        = {{C}omprehensive {T}ranscriptomic {A}nalysis in {W}ild-type
                      and {ATM} {K}nockout {L}ung {C}ancer {C}ells: {I}nfluence of
                      {C}isplatin on {O}xidative {S}tress-{I}nduced {S}enescence.},
      journal      = {Chemico-biological interactions},
      volume       = {418},
      issn         = {0009-2797},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DKFZ-2025-01027},
      pages        = {111563},
      year         = {2025},
      note         = {Volume 418, 5 September 2025, 111563},
      abstract     = {Genetic mutations and impaired DNA repair mechanisms in
                      cancer not only facilitate tumor progression but also reduce
                      the effectiveness of chemotherapeutic agents, particularly
                      cisplatin. Combination therapy has emerged as a promising
                      strategy to overcome resistance. Comprehensive
                      transcriptomic analyses, supported by integrated comparative
                      bioinformatics and experimental approaches, are essential
                      for identifying biomarkers and novel therapeutic targets
                      underlying drug resistance. In this study, we performed
                      overall survival and mutation analyses, examining 23
                      double-strand break repair proteins across more than 7,500
                      tumors spanning 23 distinct cancer types. Our findings
                      identify ATM (ataxia-telangiectasia mutated) as a key
                      protein with the highest mutation frequency. Using
                      CRISPR/Cas9, we investigated the effects of ATM mutations on
                      signalling pathways that influence the cellular response to
                      cisplatin. ATM knockout enhanced cisplatin cytotoxicity by
                      activating alternative cell death pathways, including
                      oxidative stress-induced senescence and necroptosis.
                      Microarray analysis revealed a regulatory interplay between
                      ATM and NRF2 in the activation of oxidative stress-induced
                      senescence. Specifically, ATM knockoutpromoted senescence by
                      increasing reactive oxygen species (ROS) accumulation and
                      downregulating NRF2 expression. To enhance combination
                      therapy, integrating genetic profiling with advanced tools
                      such as CRISPR/Cas9 to target oxidative stress-induced
                      senescence may provide innovative strategies to overcome
                      drug resistance, thereby advancing personalized cancer
                      treatment. These approaches lay the foundation for the
                      development of personalized cancer therapies tailored to the
                      unique mutational landscape of individual patients, offering
                      promising prospects for improving treatment outcomes.},
      keywords     = {Chemotherapy resistance (Other) / Personalized cancer
                      therapy (Other) / Prognostic biomarkers Signal transduction
                      (Other) / Survival analysis (Other) / Transcriptomics
                      (Other)},
      cin          = {B063},
      ddc          = {540},
      cid          = {I:(DE-He78)B063-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40383470},
      doi          = {10.1016/j.cbi.2025.111563},
      url          = {https://inrepo02.dkfz.de/record/301485},
}