% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Huang:303026,
      author       = {D. Huang and Z. Xiong and B. Zhong and X. Li and S. A.
                      Mohamed and J. Sun and H. Xu and J. Guo and Z. Deng and X.
                      Li$^*$ and K. Almhanna and Y. Chen and L. Lian},
      title        = {{CDK}12 inhibition enhances oxaliplatin efficacy in gastric
                      cancer by suppressing the {MAPK} signaling pathway.},
      journal      = {Journal of gastrointestinal oncology},
      volume       = {16},
      number       = {3},
      issn         = {2078-6891},
      address      = {Hong Kong},
      publisher    = {Pioneer Bioscience Publ.},
      reportid     = {DKFZ-2025-01473},
      pages        = {823 - 839},
      year         = {2025},
      abstract     = {Gastric cancer (GC) is a leading cause of cancer-related
                      mortality worldwide. Oxaliplatin (OXA) based therapy
                      plus/minus targeted therapy and immune check point
                      inhibitors is the standard first-line treatment for advanced
                      GC; however, its clinical efficacy is often hindered by the
                      development of drug resistance. Cyclin-dependent kinase 12
                      (CDK12), a transcriptional regulator linked to DNA repair,
                      plays a crucial role in transcription, cancer progression as
                      well as drug resistance, where its exact role is unclear. In
                      this study, we will investigate the role of CDK12 in GC
                      progression and its potential as a therapeutic target
                      specifically to enhance the efficacy of OXA.CDK12 expression
                      in GC tissues was analyzed by quantitative polymerase chain
                      reaction (qPCR) and tissue microarrays (TMAs). A
                      Kaplan-Meier survival analysis was conducted to assess the
                      relationship between CDK12 levels and clinical outcomes. The
                      effect of the CDK12 inhibitor combined with OXA was
                      evaluated through in vivo and in vitro models.
                      RNA-sequencing and western blots were used to investigate
                      the molecular mechanisms of CDK12 inhibitor sensitizing
                      OXA.CDK12 exhibited significant amplification frequency in
                      GC. The Mendelian-randomization analysis revealed a positive
                      causal association between elevated CDK12 expression and an
                      increased risk of GC. Additionally, CDK12 was significantly
                      overexpressed in GC tissues compared with adjacent normal
                      tissues, and its high expression was significantly
                      associated with a worse prognosis. The functional assays
                      revealed that combining the CDK12 inhibitor THZ531 with OXA
                      synergistically suppressed GC cell proliferation, induced
                      apoptosis, and reduced colony formation in vitro, while
                      substantially inhibiting tumor growth in xenograft models.
                      Mechanistically, CDK12 inhibition disrupted MAPK signaling,
                      leading to enhanced OXA-induced DNA damage and potentiated
                      anti-tumor effects.Our findings suggest that CDK12
                      inhibition may represent a promising strategy for overcoming
                      OXA resistance and improving GC treatment outcomes.},
      keywords     = {Gastric cancer (GC) (Other) / cell cycle (Other) /
                      combination therapy (Other) / cyclin-dependent kinase 12
                      (CDK12) (Other) / oxaliplatin (OXA) (Other)},
      cin          = {C070},
      ddc          = {610},
      cid          = {I:(DE-He78)C070-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40672076},
      pmc          = {pmc:PMC12261016},
      doi          = {10.21037/jgo-2025-392},
      url          = {https://inrepo02.dkfz.de/record/303026},
}