Inhibition of Focal Adhesion Kinase as an anti-metastatic therapy

Abstract

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has a physiological role in cell migration, cell survival, wound healing, and cell cycle progression, via both kinase-dependent and kinase-independent functions. However, FAK deregulation, manifested as increased or aberrant expression and/or activation is observed in several types of cancer, including colon, breast, thyroid and pancreatic cancer. In addition, FAK has also been implicated in various metastatic processes, including focal adhesion turnover, invasion and epithelial to mesenchymal transition of tumor cells. Therefore, FAK has become an attractive target for anti-metastatic therapies. FAK inhibitors have been developed, with varying degrees of success, including small molecule ATP-competitive inhibitors, allosteric FAK inhibitors, scaffolding FAK inhibitors, siRNA against FAK, dominant-negative constructs, peptides, and antibodies. These inhibitors can selectively block FAK phosphorylation and downstream activation. Most of them inhibit FAK-induced cell migration and invasion and enhance cell apoptosis. Furthermore, some inhibitors cause cell cycle arrest and inhibition of angiogenesis. In fact, the combination of FAK inhibitors with already existing chemotherapeutic agents enhances anti-tumor responses. Thus, FAK inhibitors seem to be a very promising strategy for cancer therapy. This thesis will focus on analyzing the role of FAK during cancer and metastasis, through interactions with other molecules and pathways. In addition, the thesis will address the current status and future perspectives of the most promising FAK inhibitors.