It is twenty years since Focal Adhesion Kinase (FAK) was found to be overexpressed in many types of human cancer. FAK plays an important role in adhesion, spreading, motility, invasion, metastasis, survival, angiogenesis, and recently has been found to play an important role as well in epithelial to mesenchymal transition (EMT), cancer stem cells and tumor microenvironment. FAK has kinase-dependent and kinase independent scaffolding, cytoplasmic and nuclear functions. Several years ago FAK was proposed as a potential therapeutic target; the first clinical trials were just reported, and they supported further studies of FAK as a promising therapeutic target. This review discusses the main functions of FAK in cancer, and specifically focuses on recent novel findings on the role of FAK in cancer stem cells, microenvironment, epithelial-to-mesenchymal transition, invasion, metastasis, and also highlight new approaches of targeting FAK and critically discuss challenges that lie ahead for its targeted therapeutics. The review provides a summary of translational approaches of FAK-targeted and combination therapies and outline perspectives and future directions of FAK research.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that resides at the sites of at focal adhesions. The 125 kDa FAK protein is encoded by the FAK gene located on human chromosome 8q24. Structurally, FAK consists of an amino-terminal regulatory FERM domain, a central catalytic kinase domain, and a carboxy-terminal focal adhesion targeting domain. FAK has been shown to be an important mediator of cell adhesion, growth, proliferation, survival, angiogenesis and migration, all of which are often disrupted in cancer cells. Normal tissues have low expression of FAK, while primary and metastatic tumors significantly overexpress this protein. This review summarizes expression of FAK by immunohistochemical staining in different tumor types and presents several FAK inhibition therapy approaches.

Focal adhesion kinase (FAK) is a protein tyrosine kinase that is overexpressed in most solid types of tumors and plays an important role in the survival signaling. Recently, we have developed a novel computer modeling combined with a functional assay approach to target the main autophosphorylation site of FAK (Y397). Using these approaches, we identified 1-(2-hydroxyethyl)-3, 5, 7-triaza-1-azoniatricyclo [3.3.1.1 ^3,7 ]decane; bromide, called Y11, a small molecule inhibitor targeting Y397 site of FAK. Y11 significantly and specifically decreased FAK autophosphorylation, directly bound to the N-terminal domain of FAK. In addition, Y11 decreased Y397-FAK autophosphorylation, inhibited viability and clonogenicity of colon SW620 and breast BT474 cancer cells and increased detachment and apoptosis in vitro . Moreover, Y11 significantly decreased tumor growth in the colon cancer cell mouse xenograft model. Finally, tumors from the Y11-treated mice demonstrated decreased Y397-FAK autophosphorylation and activation of poly (ADP ribose) polymerase and caspase-3. Thus, targeting the major autophosphorylation site of FAK with Y11 inhibitor is critical for development of cancer therapeutics and carcinogenesis field.

Malignant gliomas are characterized by aggressive tumor growth with a mean survival of 15 to 18 months and frequently developed resistance to temozolomide. Therefore, strategies that sensitize glioma cells to temozolomide have a high translational impact. We have studied focal adhesion kinase (FAK), a tyrosine kinase and emerging therapeutic target that is known to be highly expressed and activated in glioma. In this report, we tested the FAK autophosphorylation inhibitor, Y15, in DBTRG and U87 glioblastoma cells. Y15 significantly decreased viability and clonogenicity in a dose-dependent manner, increased detachment in a dose- and time-dependent manner, caused apoptosis, and inhibited cell invasion in both cell lines. In addition, Y15 treatment decreased autophosphorylation of FAK in a dose-dependent manner and changed cell morphology by causing cell rounding in DBTRG and U87 cells. Administration of Y15 significantly decreased subcutaneous DBTRG tumor growth with decreased Y397-FAK autophosphorylation, activated caspase-3 and PARP. Y15 was administered in an orthotopic glioma model, leading to an increase in mouse survival. The combination of Y15 with temozolomide was more effective than either agent alone in decreasing viability and activating caspase-8 in DBTRG and U87 cells in vitro. In addition, the combination of Y15 and temozolomide synergistically blocked U87 brain tumor growth in vivo. Thus, pharmacologic blockade of FAK autophosphorylation with the oral administration of a small-molecule inhibitor Y15 has a potential to be an effective therapy approach for glioblastoma either alone or in combination with chemotherapy agents such as temozolomide. Mol Cancer Ther; 12(2); 162–72. ©2012 AACR.

Human cancer is characterized by a process of tumor cell motility, invasion, and metastasis. One of the critical tyrosine kinases that is linked to these processes of tumor invasion and survival is the Focal Adhesion Kinase (FAK). Our laboratory was the first to isolate FAK from human tumors, and we had demonstrated that FAK mRNA was up-regulated in invasive and metastatic human breast and colon cancer samples. We have cloned FAK promoter and have found that FAK promoter contains p53 binding sites, and that p53 inhibits FAK transcription and regulates its expression in tumor samples. In addition, we have found a high correlation between FAK overexpression and p53 mutations in 600 population-based series of breast cancer patients. found that N-myc binds FAK promoter and induces FAK transcription in neuroblastoma cells. Thus, this review will be focused on FAK and p53 signal transduction pathways in cancer.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in survival signaling. FAK has been shown to be overexpressed in breast cancer tumors at early stages of tumorigenesis.