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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Gastric cancer (GC) presents a significant global health challenge, with advanced stages having suboptimal treatment outcomes.
• The Wnt/β-catenin signaling pathway is frequently dysregulated in GC, driving tumor progression.
• Targeting this pathway offers a potential therapeutic strategy for GC.

Purpose of the Study:

• To investigate the anti-tumor effects of PKF118-310, a Wnt/β-catenin signaling inhibitor.
• To evaluate PKF118-310 efficacy in gastric cancer cell lines, patient-derived organoids (PDOs), and patient-derived xenograft (PDX) models.

Main Methods:

• PKF118-310 treatment of GC cell lines and normal gastric epithelial cells (GES-1).
• Assessment of cellular effects including proliferation, cell cycle, apoptosis, migration, and colony formation.
• Evaluation in PDOs and PDX models, with transcriptome sequencing for Tcf7 gene expression analysis.

Main Results:

• PKF118-310 significantly inhibited GC cell proliferation, migration, invasion, and colony formation in a dose- and time-dependent manner.
• The compound induced G1-phase cell cycle arrest and apoptosis, down-regulating Wnt/β-catenin target genes and cancer stem cell (CSC) markers.
• Tcf7 expression correlated with sensitivity in PDOs, and PKF118-310 reduced tumor growth in PDX models without significant toxicity.

Conclusions:

• PKF118-310 demonstrates potent anti-tumor activity against gastric cancer by inhibiting Wnt/β-catenin signaling.
• The drug effectively targets CSCs and reduces tumor growth in preclinical models.
• PKF118-310 represents a promising therapeutic candidate for gastric cancer treatment.