Targeting focal adhesion kinase: from molecular mechanisms to next-generation cancer therapeutics

Focal adhesion kinase (FAK) is a key cytoplasmic tyrosine kinase that transmits signals from integrins and growth factors to control cell migration, metastasis, growth and survival. FAK can modulate prominent oncogenic pathways, such as the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) and Rat Sarcoma virus/extracellular signal-regulated kinase (Ras/ERK) pathway, through autophosphorylation at Y397 and subsequent conformational activation. Notably, FAK is overexpressed and activated in many solid tumors. Its expression levels are correlated with tumor stage, lymph node metastasis, and poor prognosis. Moreover, FAK promotes tumor malignancy by inducing epithelial-mesenchymal transition (EMT), chemoresistance, and stemness properties. However, targeting FAK is considerably challenging owing to signal complexity. To date, only eight small-molecule FAK inhibitors have reached the clinical trial stage, mainly in combination with chemotherapy, targeted therapy, or immunotherapy. Recent advances, such as proteolysis-targeting chimeras (PROTACs) degraders, protein-protein interaction (PPI) blockers, allosteric inhibitors, and natural products, offer promising opportunities to overcome current therapeutic challenges. The present review provides a comprehensive discussion of FAK, ranging from its structure and regulatory mechanisms to its central role in tumor malignancy and the current status of inhibitor development, aiming to inform future translational efforts in solid tumors.