From tumorigenesis to microenvironment and immunoregulation: the many faces of focal adhesion kinase and challenges associated with targeting this elusive protein

Focal adhesion kinase (FAK) has long been confirmed to have a major role in cancer as it involved in virtually every aspect of tumorigenesis and tumor progression (1,2). Known for being significantly overexpressed in over 80% of solid tumors, and even hematological cancers (3,4), FAK drives tumorigenesis by regulating many of the traditional hallmarks of cancer (5,6). Research continues to demonstrate FAK’s involvement in multiple aspects of cancer, primarily due to the role of FAK as an oncogenic scaffold (7). FAK has docking sites at both the N- and C-termini of the protein, allowing these regions to interact with a multitude of binding partners driving proliferation, survival, invasion/migration, and angiogenesis. As FAK expression is minimal in surrounding normal tissue, these phenotypes are a defining characteristic of FAK overexpression in cancer. Additionally, FAK plays a role in the sequestration of pro-apoptotic proteins (8), the manipulation of the tumor microenvironment (TME) (9), the immune response (10), and anoikis (11), all of which demonstrate the importance of FAK as a continually evolving, multifaceted protein in tumor biology.