Elsevier

Pharmacology & Therapeutics

Volume 146, February 2015, Pages 132-149
Pharmacology & Therapeutics

Associate editor: B. Teicher
FAK signaling in human cancer as a target for therapeutics

https://doi.org/10.1016/j.pharmthera.2014.10.001Get rights and content

Abstract

Focal adhesion kinase (FAK) is a key regulator of growth factor receptor- and integrin-mediated signals, governing fundamental processes in normal and cancer cells through its kinase activity and scaffolding function. Increased FAK expression and activity occurs in primary and metastatic cancers of many tissue origins, and is often associated with poor clinical outcome, highlighting FAK as a potential determinant of tumor development and metastasis. Indeed, data from cell culture and animal models of cancer provide strong lines of evidence that FAK promotes malignancy by regulating tumorigenic and metastatic potential through highly-coordinated signaling networks that orchestrate a diverse range of cellular processes, such as cell survival, proliferation, migration, invasion, epithelial–mesenchymal transition, angiogenesis and regulation of cancer stem cell activities. Such an integral role in governing malignant characteristics indicates that FAK represents a potential target for cancer therapeutics. While pharmacologic targeting of FAK scaffold function is still at an early stage of development, a number of small molecule-based FAK tyrosine kinase inhibitors are currently undergoing pre-clinical and clinical testing. In particular, PF-00562271, VS-4718 and VS-6063 show promising clinical activities in patients with selected solid cancers. Clinical testing of rationally designed FAK-targeting agents with implementation of predictive response biomarkers, such as merlin deficiency for VS-4718 in mesothelioma, may help improve clinical outcome for cancer patients. In this article, we have reviewed the current knowledge regarding FAK signaling in human cancer, and recent developments in the generation and clinical application of FAK-targeting pharmacologic agents.

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.

References (276)

  • H.C. Chen et al.

    Interaction of focal adhesion kinase with cytoskeletal protein talin

    J Biol Chem

    (1995)
  • H.C. Chen et al.

    Tyrosine phosphorylation of focal adhesion kinase stimulated by hepatocyte growth factor leads to mitogen-activated protein kinase activation

    J Biol Chem

    (1998)
  • X.L. Chen et al.

    VEGF-induced vascular permeability is mediated by FAK

    Dev Cell

    (2012)
  • D. Chodniewicz et al.

    Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffold

    Biochim Biophys Acta

    (2004)
  • C. Cicchini et al.

    TGFbeta-induced EMT requires focal adhesion kinase (FAK) signaling

    Exp Cell Res

    (2008)
  • S.R. Datta et al.

    Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery

    Cell

    (1997)
  • Q. Ding et al.

    p27Kip1 and cyclin D1 are necessary for focal adhesion kinase regulation of cell cycle progression in glioblastoma cells propagated in vitro and in vivo in the scid mouse brain

    J Biol Chem

    (2005)
  • M.S. Duxbury et al.

    RNA interference targeting focal adhesion kinase enhances pancreatic adenocarcinoma gemcitabine chemosensitivity

    Biochem Biophys Res Commun

    (2003)
  • M.S. Duxbury et al.

    Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells

    Surgery

    (2004)
  • H. Fan et al.

    Function of focal adhesion kinase scaffolding to mediate endophilin A2 phosphorylation promotes epithelial–mesenchymal transition and mammary cancer stem cell activities in vivo

    J Biol Chem

    (2013)
  • X.Q. Fang et al.

    Somatic mutational analysis of FAK in breast cancer: a novel gain-of-function mutation due to deletion of exon 33

    Biochem Biophys Res Commun

    (2014)
  • S.M. Frisch et al.

    Integrins and anoikis

    Curr Opin Cell Biol

    (1997)
  • T. Fujii et al.

    Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor

    J Hepatol

    (2004)
  • V.M. Golubovskaya et al.

    Focal adhesion kinase and p53 signaling in cancer cells

    Int Rev Cytol

    (2007)
  • V.M. Golubovskaya et al.

    Direct interaction of the N-terminal domain of focal adhesion kinase with the N-terminal transactivation domain of p53

    J Biol Chem

    (2005)
  • V. Golubovskaya et al.

    Cloning and characterization of the promoter region of human focal adhesion kinase gene: nuclear factor kappa B and p53 binding sites

    Biochim Biophys Acta

    (2004)
  • S.L. Gupton et al.

    Spatiotemporal feedback between actomyosin and focal-adhesion systems optimizes rapid cell migration

    Cell

    (2006)
  • C.R. Hauck et al.

    v-Src SH3-enhanced interaction with focal adhesion kinase at beta 1 integrin-containing invadopodia promotes cell invasion

    J Biol Chem

    (2002)
  • S. Abbi et al.

    Regulation of focal adhesion kinase by a novel protein inhibitor FIP200

    Mol Biol Cell

    (2002)
  • M. Agochiya et al.

    Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells

    Oncogene

    (1999)
  • T. Akagi et al.

    v-Crk activates the phosphoinositide 3-kinase/AKT pathway by utilizing focal adhesion kinase and H-Ras

    Mol Cell Biol

    (2002)
  • A.N. Alexopoulou et al.

    Tumour-associated endothelial-FAK correlated with molecular sub-type and prognostic factors in invasive breast cancer

    BMC Cancer

    (2014)
  • M. Al-Hajj et al.

    Prospective identification of tumorigenic breast cancer cells

    Proc Natl Acad Sci U S A

    (2003)
  • B. Al-Lazikani et al.

    Combinatorial drug therapy for cancer in the post-genomic era

    Nat Biotechnol

    (2012)
  • E.A. Almeida et al.

    Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase

    J Cell Biol

    (2000)
  • E. Avizienyte et al.

    Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling

    Nat Cell Biol

    (2002)
  • C.M. Bagi et al.

    Sunitinib and PF-562,271 (FAK/Pyk2 inhibitor) effectively block growth and recovery of human hepatocellular carcinoma in a rat xenograft model

    Cancer Biol Ther

    (2009)
  • C.M. Bagi et al.

    Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on bone tumors: implications for bone metastases

    Cancer

    (2008)
  • S. Barbero et al.

    Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis

    Cancer Res

    (2009)
  • E.A. Beierle et al.

    TAE226 inhibits human neuroblastoma cell survival

    Cancer Investig

    (2008)
  • R.B. Birge et al.

    Identification and characterization of a high-affinity interaction between v-Crk and tyrosine-phosphorylated paxillin in CT10-transformed fibroblasts

    Mol Cell Biol

    (1993)
  • J. Bottsford-Miller et al.

    Enhancing anti-angiogenic therapy by blocking focal adhesion kinase

    Cancer Res

    (2011)
  • V. Bouchard et al.

    Fak/Src signaling in human intestinal epithelial cell survival and anoikis: differentiation state-specific uncoupling with the PI3-K/Akt-1 and MEK/Erk pathways

    J Cell Physiol

    (2007)
  • K. Brami-Cherrier et al.

    FAK dimerization controls its kinase-dependent functions at focal adhesions

    EMBO J

    (2014)
  • E. Brugnera et al.

    Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex

    Nat Cell Biol

    (2002)
  • V.G. Brunton et al.

    A role for epidermal growth factor receptor, c-Src and focal adhesion kinase in an in vitro model for the progression of colon cancer

    Oncogene

    (1997)
  • K. Burridge et al.

    Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly

    J Cell Biol

    (1992)
  • X. Cai et al.

    Spatial and temporal regulation of focal adhesion kinase activity in living cells

    Mol Cell Biol

    (2008)
  • M.B. Calalb et al.

    Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases

    Mol Cell Biol

    (1995)
  • W.G. Cance et al.

    Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes

    Clin Cancer Res

    (2000)
  • Cited by (318)

    View all citing articles on Scopus
    1

    Present address: Cancer Research UK Manchester Institute, The University of Manchester, Manchester, M20 4BX, UK.

    View full text