Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that drives tumour growth and metastasis through kinase-dependent and kinase-independent pathways.
FAK promotes metastasis by regulating processes involved in tumour cell motility and invasion, including control of focal adhesion and cytoskeletal dynamics, as well as the regulation of matrix metalloproteinase (MMP) surface expression.
Tumour growth is enhanced through pro-proliferative and anti-apoptotic functions of FAK.
FAK is connected to cancer stem cell and progenitor cell maintenance through kinase-dependent and kinase-independent functions. FAK signals contribute to the malignant outgrowth of these cells.
FAK favours tumour progression via the regulation of signalling pathways within cells of the tumour microenvironment, such as endothelial cells, haematopoietic cells, platelets, macrophages and fibroblasts.
FAK activity promotes endothelial cell migration, proliferation and survival, and it stimulates tumour angiogenesis. FAK-mediated regulation of endothelial cell permeability can influence tumour metastasis.
FAK expression and activity in tumour and endothelial cells is frequently upregulated and correlated with a poor patient prognosis.
Several molecules that target FAK kinase activity or its kinase-independent scaffolding function are under investigation in preclinical trials. Promising drug candidates in Phase I or II clinical trials are small molecule ATP-competitive inhibitors.
Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. FAK promotes tumour progression and metastasis through effects on cancer cells, as well as stromal cells of the tumour microenvironment. The kinase-dependent and kinase-independent functions of FAK control cell movement, invasion, survival, gene expression and cancer stem cell self-renewal. Small molecule FAK inhibitors decrease tumour growth and metastasis in several preclinical models and have initial clinical activity in patients with limited adverse events. In this Review, we discuss FAK signalling effects on both tumour and stromal cell biology that provide rationale and support for future therapeutic opportunities.
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Goodwin, J. M. et al. An AMPK-Independent Signaling Pathway Downstream of the LKB1 Tumor Suppressor Controls Snail1 and Metastatic Potential. Mol. Cell http://dx.doi.org/10.1016/j.molcel.2014.06.021 (2014).
The authors apologize to those whose work on focal adhesion kinase (FAK) signalling has advanced the field but could not be cited owing to journal limitations. Studies in the Schlaepfer laboratory are funded by US National Institutes of Health (NIH) grants CA102310 and CA180769. F.J.S. is supported by an NIH training grant (T32-CA121938). C.J. is supported by an American Heart Association fellowship (12POST11760014). The authors thank J. Pachter, Head of Research at Verastem Inc., for insightful discussions of ongoing FAK inhibitor clinical trials. The authors also thank C. Lawson, N. L. Miller and I. Tancioni for discussions and help in revising the manuscript.
The authors declare no competing financial interests.
- Integrin receptor clustering
The formation of multimeric membrane integrin clusters upon binding to extracellular matrix ligands, inducing the formation of multi-protein complexes at cytoplasmic integrin tails to drive focal adhesion formation and cytoskeletal rearrangement.
- Focal adhesions
Multi-protein complexes that regulate cellular attachment by linking the actin cytoskeleton to components of the extracellular matrix via transmembrane receptors termed integrins.
- Epithelial-to-mesenchymal transition
(EMT). A cellular mechanism that allows polarized epithelial cells to acquire a mesenchymal phenotype that is characterized by increased cell migration and invasion and the ability to survive in adhesion-independent conditions.
- Floxed mouse models
Transgenic insertion of loxP sites flanking a gene of interest. Induced expression of Cre recombinase catalyses recombination between the loxP repeats and mediates the deletion of the gene of interest.
- MMTV–PyMT model
A mouse model with conditional expression of the polyomavirus middle T antigen (PyMT) under the control of the mouse mammary tumour virus (MMTV) promoter, inducing the formation of mammary tumours.
- Guanine nucleotide exchange factor
(GEF). A protein that promotes the exchange of GDP for GTP on a GTPase, thereby facilitating its activation.
Specialized membrane protrusions (also known as an invasive pseudopodia) in which active extracellular matrix degradation takes place.
A seven-subunit protein complex that is involved in regulation of the actin cytoskeleton; it mediates the nucleation of branched actin filaments.
- Neural Wiskott–Aldrich syndrome protein
(N-WASP). A protein that promotes actin polymerization by stimulating the activity of the ARP2/3 complex.
Cell death (apoptosis) that is induced by the loss of cell matrix adhesion and a physiological mechanism to prevent cell displacement.
A collection of cells arising from a single cell of mammary origin through clonal growth in culture.
- Vascular normalization
The process of restoring normal vasculature from the classical cancer-associated tortuous and leaky vessels. This phenomenon involves increased vascular pericyte coverage and decreased vascular permeability and hypoxia, and it results in decreased metastasis and increased blood perfusion, rendering vessels more efficient for oxygen and drug delivery.
- Tumour cell extravasation
The crucial step in tumour metastasis in which tumour cells exit the vasculature to penetrate target organs. This requires tumour cell adhesion to the endothelium, spreading out across endothelial cells, and penetration of the basement membrane.
- ATP site hinge
A segment that connects the two lobes of a kinase domain. Hinge and kinase lobes form an interface that creates the ATP-binding pocket.
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Sulzmaier, F., Jean, C. & Schlaepfer, D. FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer 14, 598–610 (2014). https://doi.org/10.1038/nrc3792
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