Focal adhesion kinase: from biological functions to therapeutic strategies

Abstract

Focal adhesion kinase (FAK), a nonreceptor cytoplasmic tyrosine kinase, is a vital participant in primary cellular functions, such as proliferation, survival, migration, and invasion. In addition, FAK regulates cancer stem cell activities and contributes to the formation of the tumor microenvironment (TME). Importantly, increased FAK expression and activity are strongly associated with unfavorable clinical outcomes and metastatic characteristics in numerous tumors. In vitro and in vivo studies have demonstrated that modulating FAK activity by application of FAK inhibitors alone or in combination treatment regimens could be effective for cancer therapy. Based on these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. This article briefly describes the structure and function of FAK, as well as research progress on FAK inhibitors in combination therapies. We also discuss the challenges and future directions regarding anti-FAK combination therapies.

Keywords: Combination therapy; Focal adhesion kinase; Immunotherapy; Tumor microenvironment.

Fig. 1

Schematic diagram of the structural domain of FAK. FAK comprises three primary components, including a central kinase domain, a FERM domain on the N-terminal side, and a FAT domain on the C-terminal side. The kinase domain, which is crucial for catalytic activity, is flanked by three proline-rich regions that are responsible for protein‒protein interactions. The FAK phosphorylation sites and important binding proteins that regulate FAK activity and downstream signaling are highlighted in the diagram

Fig. 2

FAK-mediated signaling cascades involved in tumor progression. FAK activation is multifaceted and can be mediated by various factors, such as integrins, receptor tyrosine kinases (RTKs), mechanical stimuli, cytokines, G-protein-coupled receptors (GPCRs), and a change in intracellular pH (H+). Upon phosphorylation, FAK may induce the activation of different transduction pathways, including RAS/RAF/ERK, JNK, YAP, and PI3K/AKT/mTOR signaling. This process can lead to the regulation of relevant oncogenes, which in turn supports cancer cell survival. FAK also exerts nuclear functions, acting as a scaffold for p53 and Mdm2 while also promoting the polyubiquitination and degradation of p53. In doing so, FAK again promotes resistance to apoptosis. As shown in the diagram, the highlighted red boxes indicate targets of interest for the development of combination therapy using FAK inhibitors

Fig. 3

The role of FAK in the tumor microenvironment. FAK not only maintains cancer malignancy but also influences remodeling of the immune microenvironment. For example, FAK can recruit immune cells, cancer-associated fibroblasts, and endothelial cells and even remodel the extracellular matrix. Preclinical studies support the importance of FAK inhibitors in combination with other immunotherapies, and relevant clinical trials are in progress, demonstrating the importance of FAK in oncology treatment