2. Academic Validation
  3. CDK1 drives SOX9-mediated chemotherapeutic resistance in gastric cancer

CDK1 drives SOX9-mediated chemotherapeutic resistance in gastric cancer

  • J Exp Clin Cancer Res. 2025 Oct 8;44(1):284. doi: 10.1186/s13046-025-03523-3.
Marwah Al-Mathkour 1,  Zheng Chen 1,  Julio Poveda 2,  Longlong Cao 1 3,  Oliver G McDonald 2 4,  Dunfa Peng 1,  Mohammed Soutto 1 5,  Zhibin Chen 6 4,  Heng Lu 1,  Yan Guo 7 4,  Shria Kumar 8 4,  Alexander Zaika 1 5 4,  Silvia Giordano 9,  Shoumin Zhu 10,  Wael El-Rifai 11 12 13
Affiliations

Affiliations

  • 1 Department of Surgery, Miller School of Medicine, University of Miami, 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA.
  • 2 Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 3 Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
  • 4 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 5 Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA.
  • 6 Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 7 Department of Public Health, Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 8 Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 9 Department of Oncology, University of Torino and Candiolo Cancer Institute, Candiolo, Italy.
  • 10 Department of Surgery, Miller School of Medicine, University of Miami, 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA. sxz489@miami.edu.
  • 11 Department of Surgery, Miller School of Medicine, University of Miami, 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA. welrifai@med.miami.edu.
  • 12 Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA. welrifai@med.miami.edu.
  • 13 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA. welrifai@med.miami.edu.
PMID: 41063222 DOI: 10.1186/s13046-025-03523-3
Abstract

Background: Gastric carcinoma ranks as the fifth most common cause of cancer-related mortality globally. Chemoresistance remains a critical barrier to treatment efficacy, driving poor survival outcomes in gastric Cancer patients. Cyclin-dependent kinase 1 (CDK1) is overexpressed in several malignancies. SOX9 transcription factor plays critical roles in gastric tumorigenesis and therapeutic resistance. This study identifies a CDK1-SOX9-BCL-xL signaling axis as an important mediator of chemoresistance in gastric Cancer.

Methods: Bioinformatics and computational approaches were used for analysis of human and mouse public and local data sets. Chromatin immunoprecipitation (ChIP), western blotting, quantitative PCR (qPCR), immunofluorescence, and immunohistochemistry assays were applied in the study. The study utilized a number of in vitro models including cell lines and patient-derived tumoroids. The in vivo models included patient-derived xenograft (PDX), the Tff1 knockout, and CDK1 conditional knockout mouse models.

Results: Our study identified concurrent overexpression of CDK1 and SOX9 in gastric Cancer patients. Genetic knockdown and pharmacological inhibition of CDK1 suppressed SOX9 protein levels and transcriptional activity in vitro and in vivo. Mechanistically, CDK1 regulates SOX9 through a miR-145-dependent epigenetic axis: CDK1-mediated phosphorylation and activation of DNMT1 to drive methylation-dependent silencing of miR-145, thereby relieving miR-145's repression of SOX9. Strikingly, both CDK1 and SOX9 were upregulated in cisplatin-resistant gastric Cancer cell lines. We further identified Bcl-xL as a direct transcriptional target of SOX9, functionally mediating cisplatin resistance. CDK1 inhibition using dinaciclib re-sensitized resistant models to cisplatin by disrupting the CDK1-SOX9-BCL-xL pathway, underscoring its central role in chemoresistance. In PDX models, combining dinaciclib with cisplatin synergistically reduced tumor volume, and extended survival compared to monotherapies, highlighting the therapeutic potential.

Conclusion: This study elucidates the epigenetic and transcriptional mechanisms driving the CDK1-SOX9-BCL-xL axis in gastric Cancer chemoresistance. Pharmacological inhibition of CDK1 effectively disrupts this axis, restoring cisplatin sensitivity and suppressing tumor growth in gastric Cancer models. The observed synergy between dinaciclib and cisplatin underscores a promising therapeutic strategy to overcome chemoresistance in gastric Cancer.

Keywords

BCL-xL; CDK1; Gastric cancer; SOX9.

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