2. Academic Validation
  3. CEA-induced PI3K/AKT pathway activation through the binding of CEA to KRT1 contributes to oxaliplatin resistance in gastric cancer

CEA-induced PI3K/AKT pathway activation through the binding of CEA to KRT1 contributes to oxaliplatin resistance in gastric cancer

  • Drug Resist Updat. 2025 Jan:78:101179. doi: 10.1016/j.drup.2024.101179.
Yifan Chen 1,  Yulong Mi 1,  Song Tan 1,  Yizhen Chen 1,  Shaolin Liu 1,  Shengtao Lin 1,  Changshun Yang 1,  Weifeng Hong 2,  Weihua Li 3
Affiliations

Affiliations

  • 1 Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350013, China; Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou 350001, China.
  • 2 Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou 310005, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310005, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou 310005, China. Electronic address: hongweifeng413@163.com.
  • 3 Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350013, China; Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou 350001, China. Electronic address: liwh@fjmu.edu.cn.
PMID: 39644827 DOI: 10.1016/j.drup.2024.101179
Abstract

Background: The serum level of carcinoembryonic antigen (CEA) has prognostic value in patients with gastric Cancer (GC) receiving oxaliplatin-based chemotherapy. As the molecular functions of CEA are increasingly uncovered, its role in regulating oxaliplatin resistance in GC attracts attention.

Methods: The survival analysis adopted the KaplanMeier method. Effects of CEA on proliferative capacity were investigated using CCK8, colony formation, and xenograft assays. Oxaliplatin sensitivity was identified through IC50 detection, Apoptosis analysis, comet assay, Organoid culture model, and xenograft assay. Multi-omics approaches were utilized to explore CEA's downstream effects. The binding of CEA to KRT1 was confirmed through proteomic analysis and Co-IP, GST pull-down, and immunofluorescence colocalization assays. Furthermore, small molecule inhibitors were identified using virtual screening and surface plasmon resonance.

Results: Starting from clinical data, we confirmed that CEA demonstrated superior ability to predict the prognosis of patients with GC who received oxaliplatin-based chemotherapy, particularly in predicting recurrence-free survival based on serum CEA level. In vitro and in vivo experiments revealed CEAhigh GC cells presented increased proliferative capacity and decreased oxaliplatin sensitivity. The resistance phenotype was transmitted through secreted CEA. Multi-omics analysis revealed that CEA activated the PI3K/Akt pathway by binding to KRT1, leading to oxaliplatin resistance. Finally, the small molecule inhibitor evacetrapib, which competitively inhibits the CEA-KRT1 interaction, was identified and validated in vitro.

Conclusions: In summary, the CEA-KRT1-PI3K/Akt axis regulates oxaliplatin sensitivity in GC cells. Treatment with small molecule inhibitors such as evacetrapib to inhibit this interaction constitutes a novel therapeutic strategy.

Keywords

Carcinoembryonic Antigen; Gastric Cancer; Oxaliplatin Resistance; PI3K/AKT Pathway.

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