<i>Frizzled-7</i> Is Required for Wnt Signaling in Gastric Tumors with and Without <i>Apc</i> Mutations

A subset of patients with gastric cancer have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no <i>in vivo</i> studies investigating the potential of targeting Wnt receptors for treating gastric cancer, and the specific Wnt receptor transmitting oncogenic Wnt signaling in gastric cancer is unknown. Here, we use inhibitors of Wnt/Fzd (OMP-18R5/vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and <i>ex vivo</i> organoid cultures. Pharmacologic targeting of Fzd inhibited the growth of gastric adenomas <i>in vivo</i>. We identified Fzd7 to be the predominant Wnt receptor responsible for transmitting Wnt signaling in human gastric cancer cells and mouse models of gastric cancer, whereby Fzd7-deficient cells were retained in gastric adenomas but were unable to respond to Wnt signals and consequently failed to proliferate. Genetic deletion of <i>Fzd7</i> or treatment with vantictumab was sufficient to inhibit the growth of gastric adenomas with or without mutations to <i>Apc</i>. Vantictumab is currently in phase Ib clinical trials for advanced pancreatic, lung, and breast cancer. Our data extend the scope of patients that may benefit from this therapeutic approach as we demonstrate that this drug will be effective in treating patients with gastric cancer regardless of <i>APC</i> mutation status. SIGNIFICANCE: The Wnt receptor Fzd7 plays an essential role in gastric tumorigenesis irrespective of <i>Apc</i> mutation status, therefore targeting Wnt/Fzd7 may be of therapeutic benefit to patients with gastric cancer.