Associate editor: B. TeicherFAK signaling in human cancer as a target for therapeutics
Introduction
It has been over two decades since focal adhesion kinase (FAK) was first identified as a highly phosphorylated substrate of the viral Src oncogene product (v-Src) localized to the integrin cluster of focal adhesions (Kanner et al., 1990, Schaller et al., 1992). Subsequent identification of potential links between FAK and human cancer of various types (Weiner et al., 1993) led to a plethora of studies, unraveling the molecular mechanisms by which FAK contributes to cancer development and progression. FAK is ubiquitously expressed and functions as a non-receptor cytoplasmic tyrosine kinase as well as a scaffold protein, mediating and regulating specific signals initiated at sites of integrin-mediated cell-extracellular matrix (ECM) attachment (Frame et al., 2010, Schaller, 2010), as well as those triggered by activated growth factor receptors (Saito et al., 1996, Brunton et al., 1997, Chen et al., 1998). Examination of human cancers has identified that enhanced expression of FAK transcripts (Weiner et al., 1993), protein (Owens et al., 1995, Okamoto et al., 2003, Park et al., 2010) and increased FAK activity (Hess et al., 2005) are positively correlated with metastasis and often associated with poorer clinical outcomes (Pylayeva et al., 2009). Based on these pre-clinical findings, attempts to develop FAK-targeting cancer therapeutics have primarily focused on impairing its kinase activity and scaffold function using pharmacological agents, and a number of FAK-directed small molecule inhibitors are currently undergoing clinical testing in cancer patients (Table 1).
In this article, we first review our current understanding of FAK-mediated signaling and how this contributes to cancer development and progression, and then describe the current landscape of FAK-directed cancer therapeutic strategies under pre-clinical and clinical development.
Section snippets
Structural features
The human gene encoding FAK, termed PTK2, is localized at chromosome 8q24.3, a region characterized by frequent aberrations in human cancers (Pylayeva et al., 2009, Schaller, 2010). FAK comprises four major domains; a central kinase domain, flanked by a N-terminal four-point-one, ezrin, radixin, moesin (FERM) domain, proline rich regions and a focal adhesion targeting (FAT) C-terminal domain (Fig. 1). Through these multi-domain structural features, FAK functions as both a protein tyrosine
Cell survival
FAK plays an integral role in tumorigenesis by promoting sustained proliferative and survival signals (Fig. 2, left panels). An association between FAK and cellular transformation was first established by Guan and Shalloway, who reported enhanced tyrosine phosphorylation of FAK in v-Src-transformed cells (Guan & Shalloway, 1992). For normal cells, disruption of integrin-mediated cell-ECM adhesion and the corresponding detachment from the substratum confers deleterious effects on cell survival
Migration
Cell migration is critical to the metastatic spread of cancer cells, and involves three fundamental steps in 2D culture environments; 1) Establishment of anterior–posterior polarity in the direction of a motility attractant, a process known as polarization; 2) Formation of cell protrusions through lamellipodia at the leading edge driven by actin polymerization, and their attachment to the substratum; 3) Cell contraction and disassembly of focal adhesions at the trailing edge of a cell, and the
FAK and cancer stem cells
Cancer stem cells refer to a subset of tumor cells that exhibit “stem-like” properties, such that they exhibit the potential to self-renew and also generate the different cell types that comprise the tumor (Visvader & Lindeman, 2008). Consequently, they contribute to intratumoral heterogeneity and sustained tumorigenesis. Cancer stem cells infrequently enter the cell cycle, and thereby constitute a subpopulation refractory to conventional cancer therapies that target rapidly dividing cells (
FAK expression in human cancers
It is now well-established that FAK expression is elevated in certain human cancers. A potential link between FAK and cancer was first reported over twenty years ago in a study that identified elevated levels of FAK transcripts in various cancer types (Weiner et al., 1993). One of 8 adenomatous tissues, 17 of 20 invasive tumors, and all 15 metastatic cancers showed increased FAK mRNA levels, whereas 6 normal tissue samples displayed no detectable FAK mRNA, suggesting that FAK overexpression may
Pharmacologic strategies targeting FAK
FAK has long been considered as a potential target for cancer therapeutics, reflecting its pivotal role in governing malignant characteristics and the evidence of high expression and activity in both preclinical cancer models and human cancers. A number of inhibitory approaches were initially employed to functionally interrogate the oncogenic role of FAK. These included antisense oligonucleotide (Sonoda et al., 1997, Judson et al., 1999), siRNA- (Ding et al., 2005, Huang et al., 2005, Tilghman
Conclusions and future perspectives
In this review, we have highlighted current knowledge and emerging findings regarding the effects of FAK signaling on cancer development and progression, and its potential as a target for cancer therapeutics. Although FAK was first identified over twenty years ago, research on this multifunctional kinase and scaffold continues apace, and is still providing significant surprises. For example, it is now apparent that FAK signals in several cellular subcompartments, including the nucleus (
Conflict of interest
Lisa G. Horvath received an honorarium for being on the organizing committee of the Australian Pfizer Oncology Forum and attended a research forum with Pfizer in La Jolla, California paid for by Pfizer. No potential conflicts of interest were disclosed by the other authors.
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Present address: Cancer Research UK Manchester Institute, The University of Manchester, Manchester, M20 4BX, UK.