Unlocking the Wnt pathway: Therapeutic potential of selective targeting FZD₇ in cancer

The Wnt signaling is of paramount pathophysiological importance. Despite showing promising anticancer activities in pre-clinical studies, current Wnt pathway inhibitors face complications in clinical trials resulting from on-target toxicity. Hence, the targeting of pathway component(s) that are essential for cancer but dispensable for normal physiology is key to the development of a safe Wnt signaling inhibitor. Frizzled₇ (FZD₇) is a Wnt pathway receptor that is redundant in healthy tissues but crucial in various cancers. FZD₇ modulates diverse aspects of carcinogenesis, including cancer growth, metastasis, maintenance of cancer stem cells, and chemoresistance. In this review, we describe state-of-the-art knowledge of the functions of FZD₇ in carcinogenesis and adult tissue homeostasis. Next, we overview the development of small molecules and biomolecules that target FZD₇. Finally, we discuss challenges and possibilities in developing FZD₇-selective antagonists.