Core tip: Despite ongoing development in treatment for colorectal cancer (CRC), effective markers for treatment of CRC have not been elucidated. FAK association with various kinases for progression and invasion of CRC has recently gained attention. The possibility for this association is accounted that FAK is interactions with integrins, growth factor receptors, and adjacent kinase domain. Targeting FAK is possible to explain the mechanism at the upstream level by which can mediate the expression of various survival signaling and inhibition of onco-suppressor genes as well as inducing migration and invasion of the CRC cells. Therefore, FAK could be a prognostic marker and a potential candidate target for CRC therapies.
Focal adhesion kinase (FAK) is a major integrin-dependent tyrosine phosphorylated protein and a non-receptor tyrosine kinase that is localized to cellular focal adhesions. Although there have been many studies on the role of FAK in breast cancer, its association with colorectal cancer (CRC) has recently gained attention. FAK, known as protein tyrosine kinase 2, is related to other tyrosine kinases, such as Src kinase. FAK comprises a central kinase domain between an N-terminal FERM domain and a C-terminal domain that includes the focal adhesion sequence. The construction of the N-terminal FERM domain is similar to that of cytoskeletal proteins and several tyrosine phosphatases and tyrosine kinases. This domain mediates FAK interactions with integrins and growth factor receptors and interacts with the adjacent kinase domain in FAK. The C-terminal domain contains proline-rich sequences for SH3 domain-containing proteins and acts to recruit additional signaling proteins[3,4].
The interactions between structural features of FAK and various kinases could be closely related to cancer growth, survival, and metastasis. FAK is activated by the direct interaction of the Src kinase with the integrin β cytoplasmic domain. Integrin can trigger the survival signaling of cancer cells at locations further downstream of phosphatidylinositol 3-kinase (PI3K), AKT, and the extracellular regulated kinase (ERK)[1,5]. The kinase complex with Src is reportedly affected in the activation of these survival pathways. In addition, FAK interacts with several receptor tyrosine kinases, including human epithelial growth factor receptor, c-Met, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor (VEGFR), which also mediates the survival pathway of cancer cells[2,6]. The detailed mechanism of PI3K signaling is as follows. The PI3K/AKT pathway induces the expression of apoptosis inhibitory proteins through nuclear factor kappa (NF-κ) B and protects the cells from stress-induced apoptosis. It is also associated with expression of cancer suppressor genes[5,6]. FAK promotes cell survival via suppression of p53 activation. This is mediated by the kinase-independent FAK FERM domain, and it suppresses the transcriptional activation of target genes that is mediated by p53 activation. Therefore, FAK can enhance cell survival through both kinase-dependent and-independent mechanisms. Further, the expression of an active mutant of ERK has indicated a direct role of FAK in promoting cancer growth. It is suggested that FAK signaling through the ERK pathway is needed to maintain cancer cell development. Furthermore, the kinase activity of FAK is estimated to be significant for the invasive phenotype and for cancer metastasis. FAK reportedly promotes cancer cell invasion through the regulation of matrix metalloproteinases (MMPs)[1,9]. In v-Src transformed cells, the Rac1 and JNK is activated in FAK/Src complex and is induced the MMP2 and MMP9 expression. Thus, FAK promotes increased invasiveness of cancer cells.
Of course, the various cancer-promoting mechanisms associated with FAK described above could also be implicated in the progression of CRC. Colon cells including epithelial and fibrous cells increases the FAK expression at early stages of carcinogenesis, even before the cancer has formed[1,11]. The up-regulation of FAK promotes the adhesive properties of CRC cells and their survival. FAK signaling is associated with the binding of the Rho guanine nucleotide exchange factor, and this signaling complex promotes the local invasion of colon carcinoma. The increase in FAK activation is thus related to elevated tyrosine phosphorylation and an adaptor protein, such as paxillin, involved in the growth of the CRC cells[1,2,12]. Further, FAK signaling contributes to epithelial-mesenchymal transition (EMT) profile change in CRC cells. FAK scaffolding increases, thus leading to alterations in EMT markers, including MMP-induced motility of CRC cells. Therefore, FAK acts to affect the dynamic internalization of E-cadherin in CRC cells[2,13]. Furthermore, FAK FERM overexpression can reduce steady-state p53 levels in CRC cells, particularly HCT-116 cells. As increased FAK expression is often found in early-stage CRCs, the FAK FERM-mediated cell survival pathway is expected to have an important function in the survival of CRC cells[7,14]. During cancer progression and metastasis, an anchorage-independent pathway can facilitate the spread of cells from the primary cancer site. Under these conditions, the cancer cells that show higher levels of FAK may be more resistant to apoptosis by non-integrin-associated FAK to translocate to the nucleus and prevent excessive p53 activation[2,7,15]. It is associated with that alternative-spliced transcripts encompassing the N-terminal FERM domain without the FAK kinase or C-terminal regions would be related to the progression of CRC[2,7].
Based on this scientific background, many pharmaceutical companies are taking efforts to develop FAK inhibitors. TAE-226 by Novartis exhibits nanomolar inhibitory activity toward FAK and protein tyrosine kinases and has anti-cancer activity. It particularly blocks cell proliferation and invasion and showed increased apoptosis in many xenograft animal models. Further, TAE-226 in combination with docetaxel, a microtubule stabilizer, significantly decreases angiogenesis and cancer cell invasion. Pfizer has developed PF-228 that shows more specific FAK inhibitory activity. It inhibits cancer cell migration in vitro. Pfizer has also developed PF-573, 228 compound, and the results indicated cancer growth inhibition in the colon xenograft cancer model. In addition, several other FAK inhibitors have been developed, including GSK2256098 by GlaxoSmithKline as a formulation for oral intake and VS-4718 by Poniard as an improved version of the previous product, PND-1186[17,18]. Although efficacy has been noted in non-clinical and early-stage clinical trials, the drugs have not been commercialized yet. Therefore, the FAK research on CRC is expected to gain momentum and be highly appreciated as a potential field for developing the new drugs.
The kinase-dependent function and kinase-independent ability of FAK are essential for cancer development. Multifunctional characteristics of FAK have been highlighted has modulators of numerous signal transductions in CRC cells. The established role of FAK in cancer progression and metastasis has obviously proposed that increase in FAK expression contributes a very important part in CRC development. Various inhibitors by small-molecules for targeting inhibition of FAK kinase and autophosphorylation have been produced by many pharmaceutical companies. Although some clinical trials have already been undergoing and potential efficacy has been noted, further studies must be needed to confirm if FAK expression has important role in a progression of human CRC and elaborates on the clear mechanisms and downstream effectors in the context of carcinogenicity. Taken together, based on the clinical observations, the over-expression of FAK at both transcriptional and translational levels in human CRCs would imply that targeting FAK could be a prognostic marker and a potential anticancer candidate for CRC therapy.