Evacetrapib
Repurposed as a cancer drug: evacetrapib blocks a CEA-KRT1 interaction that drives oxaliplatin resistance in gastric cancer (Drug Resist Updat 2025)
Original title: CEA-induced PI3K/AKT pathway activation through the binding of CEA to KRT1 contributes to oxaliplatin resistance in gastric cancer
A study found that carcinoembryonic antigen (CEA) predicts recurrence-free survival in gastric cancer patients treated with oxaliplatin-based chemotherapy, and that CEA-high gastric cancer cells proliferate more and resist oxaliplatin more, a resistance phenotype transmissible via secreted CEA. Multi-omics analysis showed CEA activates the PI3K/AKT pathway by binding to keratin 1 (KRT1), confirmed by co-immunoprecipitation, GST pull-down and immunofluorescence colocalisation. Virtual screening and surface plasmon resonance identified evacetrapib, the CETP inhibitor, as a small molecule that competitively blocks the CEA-KRT1 interaction, validated in vitro to restore oxaliplatin sensitivity. A drug-repurposing finding exploiting a structural property of evacetrapib unrelated to CETP inhibition, in a cancer application with no clinical trial data yet.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.