PKF118-310 as a Potential Small Molecule Inhibitor Targeting the Wnt/β-Catenin Pathway for Gastric Cancer Therapy.

[BACKGROUND/AIM] Gastric cancer (GC) remains a major public health concern both in Taiwan and worldwide. While advances in public health have reduced its incidence rate, clinical outcomes of advanced GC remain suboptimal with current standard therapy. The Wnt/β-catenin signaling pathway is frequently up-regulated in GC, promoting tumor progression. This study investigated the anti-tumor effects of PKF118-310, a small molecule inhibitor of the β-catenin-TCF/LEF interaction, in GC cell lines and patient-derived models.

[MATERIALS AND METHODS] GC cell lines and immortalized gastric epithelial GES-1 cells were treated with PKF118-310. Effects on proliferation, cell cycle, apoptosis, migration, invasion, and colony formation were assessed. Patient-derived organoids (PDOs) and xenograft (PDX) models were established to evaluate PKF118-310 efficacy. gene expression was analyzed transcriptome sequencing, and tumor growth was monitored .

[RESULTS] PKF118-310 significantly inhibited GC cell proliferation, migration, invasion, and colony formation in a dose- and time-dependent manner, with minimal toxicity to GES-1 cells. It induced G1-phase cell cycle arrest, apoptosis, and down-regulation of Wnt/β-catenin signaling target genes and cancer stem cell (CSC) markers. In PDOs, gene expression correlated with PKF118-310 sensitivity. In PDX models, PKF118-310 reduced tumor growth without affecting body weight.

[CONCLUSION] PKF118-310 exhibits potent anti-tumor effects in GC by inhibiting the Wnt/β-catenin signaling pathway, reducing tumor growth, and targeting CSCs. These findings suggest PKF118-310 as a promising therapeutic candidate for GC treatment.