Abstract
Focal adhesion kinase (FAK) and Wnt signaling pathways are important contributors to tumorigenesis in several cancers. While most results come from studies investigating these pathways individually, there is increasing evidence of a functional crosstalk between both signaling pathways during development and tumor progression. A number of FAK–Wnt interactions are described, suggesting an intricate, context-specific, and cell type-dependent relationship. During development for instance, FAK acts mainly upstream of Wnt signaling; and although in intestinal homeostasis and mucosal regeneration Wnt seems to function upstream of FAK signaling, FAK activates the Wnt/β-catenin signaling pathway during APC-driven intestinal tumorigenesis. In breast, lung, and pancreatic cancers, FAK is reported to modulate the Wnt signaling pathway, while in prostate cancer, FAK is downstream of Wnt. In malignant mesothelioma, FAK and Wnt show an antagonistic relationship: Inhibiting FAK signaling activates the Wnt pathway and vice versa. As the identification of effective Wnt inhibitors to translate in the clinical setting remains an outstanding challenge, further understanding of the functional interaction between Wnt and FAK could reveal new therapeutic opportunities and approaches greatly needed in clinical oncology. In this review, we summarize some of the most relevant interactions between FAK and Wnt in different cancers, address the current landscape of Wnt- and FAK-targeted therapies in different clinical trials, and discuss the rationale for targeting the FAK–Wnt crosstalk, along with the possible translational implications.
Highlights
Focal adhesion kinase (FAK) is a key regulator of growth factor receptor and integrin-mediated signaling that coordinates multiple fundamental processes such as migration, invasion, angiogenesis, cell survival, or epithelial–mesenchymal transition (EMT), in both normal and cancer cells
An interesting correlation between FAK and Wnt signaling was found in malignant mesothelioma (MM), an aggressive neoplasm that develops from the mesothelial cells lining the pleural, peritoneal, and pericardial cavities [83]
FAK appears to be an important regulator of the Wnt signaling pathway
Summary
Focal adhesion kinase (FAK) is a key regulator of growth factor receptor and integrin-mediated signaling that coordinates multiple fundamental processes such as migration, invasion, angiogenesis, cell survival, or epithelial–mesenchymal transition (EMT), in both normal and cancer cells Due to this prominent role in cancer, a vast number of preclinical and clinical studies have explored different strategies to block FAK signaling for therapeutic purposes. We analyze the potential therapeutic benefits of a combinatorial therapy targeting the crosstalk FAK–Wnt. FAK is a non-receptor protein tyrosine kinase that mediates growth factor- and adhesion-dependent signaling through several downstream pathways leading to cell migration, invasion, cell cycle progression, and survival [11,12,13], during both development and malignancy. Nuclear FAK has been described to control other transcriptional networks such as the inflammatory signaling pathway, immune escape, and angiogenesis; the mechanisms regulating FAK in the nucleus remains unclear [38]
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