Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

FAK in cancer: mechanistic findings and clinical applications

Nature Reviews Cancer volume 14, pages 598–610 (2014)Cite this article

Subjects

Key Points

  • 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.

Abstract

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Focal adhesion kinase (FAK) expression in cancer and FAK domain structure.
Figure 2: Connections of focal adhesion kinase (FAK) to tumour growth and metastasis.
Figure 3: Regulation of vascular permeability and extravasation processes by endothelial cell (EC) focal adhesion kinase (FAK).
Figure 4: Tumour microenvironmental impact of FAK signals.

Similar content being viewed by others

References

  1. Parsons, J. T. Focal adhesion kinase: the first ten years. J. Cell Sci. 116, 1409–1416 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Schaller, M. D. Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J. Cell Sci. 123, 1007–1013 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Zhao, J. & Guan, J. L. Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev. 28, 35–49 (2009).

    Article  PubMed  Google Scholar 

  4. Goode, E. L. et al. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nature Genet. 42, 874–879 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  6. The Cancer Genome Atlas Research Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  7. Sood, A. K. et al. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J. Clin. Invest. 120, 1515–1523 (2010). This study shows that hormonal stress (increased levels of norepinephrine) protects ovarian cancer cells from anoikis in vitro and in vivo through FAK signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ward, K. K. et al. Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression. Clin. Exp. Metastasis 30, 579–594 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Brami-Cherrier, K. et al. FAK dimerization controls its kinase-dependent functions at focal adhesions. EMBO J. 33, 356–370 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Corsi, J. M., Rouer, E., Girault, J. A. & Enslen, H. Organization and post-transcriptional processing of focal adhesion kinase gene. BMC Genomics 7, 198 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Cance, W. G. & Golubovskaya, V. M. Focal adhesion kinase versus p53: apoptosis or survival? Sci. Signal 1, e22 (2008).

    Article  Google Scholar 

  12. Ho, B. et al. Nanog increases focal adhesion kinase (FAK) promoter activity and expression and directly binds to FAK protein to be phosphorylated. J. Biol. Chem. 287, 18656–18673 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cheng, N., Li, Y. & Han, Z. G. Argonaute2 promotes tumor metastasis by way of up regulating focal adhesion kinase expression in hepatocellular carcinoma. Hepatology 57, 1906–1918 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Li, S. et al. Requirement of PEA3 for transcriptional activation of FAK gene in tumor metastasis. PLoS ONE 8, e79336 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Fang, X. Q. 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. 443, 363–369 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Yao, L. et al. An aberrant spliced transcript of focal adhesion kinase is exclusively expressed in human breast cancer. J. Transl. Med. 12, 136 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Canel, M. et al. Overexpression of focal adhesion kinase in head and neck squamous cell carcinoma is independent of fak gene copy number. Clin. Cancer Res. 12, 3272–3279 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Kong, X. et al. MicroRNA 7 inhibits epithelial-to mesenchymal transition and metastasis of breast cancer cells via targeting FAK expression. PLoS ONE 7, e41523 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mitra, S. K., Hanson, D. A. & Schlaepfer, D. D. Focal adhesion kinase: in command and control of cell motility. Nature Rev. Mol. Cell Biol. 6, 56–68 (2005).

    Article  CAS  Google Scholar 

  20. Nguyen, N., Yi, J. S., Park, H., Lee, J. S. & Ko, Y. G. Mitsugumin 53 (MG53) ligase ubiquitinates focal adhesion kinase during skeletal myogenesis. J. Biol. Chem. 289, 3209–3216 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Frame, M. C., Patel, H., Serrels, B., Lietha, D. & Eck, M. J. The FERM domain: organizing the structure and function of FAK. Nature Rev. Mol. Cell Biol. 11, 802–814 (2010).

    Article  CAS  Google Scholar 

  22. Lim, Y. et al. PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility. J. Cell Biol. 180, 187–203 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lim, S. T. et al. Pyk2 inhibition of p53 as an adaptive and intrinsic mechanism facilitating cell proliferation and survival. J. Biol. Chem. 285, 1743–1753 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Weis, S. M. et al. Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK. J. Cell Biol. 181, 43–50 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Plaza-Menacho, I. et al. Focal adhesion kinase (FAK) binds RET kinase via its FERM domain, priming a direct and reciprocal RET-FAK transactivation mechanism. J. Biol. Chem. 286, 17292–17302 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cooper, L. A., Shen, T. L. & Guan, J. L. Regulation of focal adhesion kinase by its amino-terminal domain through an autoinhibitory interaction. Mol. Cell. Biol. 23, 8030–8041 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lietha, D. et al. Structural basis for the autoinhibition of focal adhesion kinase. Cell 129, 1177–1187 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cai, X. et al. Spatial and temporal regulation of focal adhesion kinase activity in living cells. Mol. Cell. Biol. 28, 201–214 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Jung, O. et al. Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells. J. Cell Sci. 125, 5960–5973 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen, T. H., Chan, P. C., Chen, C. L. & Chen, H. C. Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition. Oncogene 30, 153–166 (2011).

    Article  PubMed  CAS  Google Scholar 

  31. Ritt, M., Guan, J. L. & Sivaramakrishnan, S. Visualizing and manipulating focal adhesion kinase regulation in live cells. J. Biol. Chem. 288, 8875–8886 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Choi, C. H., Webb, B. A., Chimenti, M. S., Jacobson, M. P. & Barber, D. L. pH sensing by FAK His58 regulates focal adhesion remodeling. J. Cell Biol. 202, 849–859 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Seong, J. et al. Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins. Proc. Natl Acad. Sci. USA 110, 19372–19377 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shibue, T., Brooks, M. W., Inan, M. F., Reinhardt, F. & Weinberg, R. A. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov. 2, 706–721 (2012). This study shows that integrin-dependent FAK activation and signalling through ERK promote the proliferation of cancer cells after extravasation into the lung.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Frisch, S. M., Schaller, M. & Cieply, B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J. Cell Sci. 126, 21–29 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, X. Y. et al. Snail1 controls epithelial-mesenchymal lineage commitment in focal adhesion kinase-null embryonic cells. J. Cell Biol. 195, 729–738 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fan, H., Zhao, X., Sun, S., Luo, M. & Guan, J. L. 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. 288, 3322–3333 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Canel, M., Serrels, A., Frame, M. C. & Brunton, V. G. E cadherin-integrin crosstalk in cancer invasion and metastasis. J. Cell Sci. 126, 393–401 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Lim, S. T. et al. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol. Cell 29, 9–22 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Luo, M. et al. Distinct FAK activities determine progenitor and mammary stem cell characteristics. Cancer Res. 73, 5591–5602 (2013). This study shows that FAK regulates MaCSCs and luminal progenitors via kinase-dependent and kinase-independent mechanisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lahlou, H. et al. Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression. Proc. Natl Acad. Sci. USA 104, 20302–20307 (2007). This study shows that mammary epithelial-specific deletion of FAK in PyMT mice prevents the progression of hyperplastic growth to malignant breast carcinomas. It shows the role of FAK in the development of in vivo breast tumours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Beggs, H. E. & Keely, P. J. Mammary epithelial-specific disruption of focal adhesion kinase retards tumor formation and metastasis in a transgenic mouse model of human breast cancer. Am. J. Pathol. 173, 1551–1565 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Luo, M. et al. Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells. Cancer Res. 69, 466–474 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pylayeva, Y. et al. Ras- and PI3K dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J. Clin. Invest. 119, 252–266 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. McLean, G. W. et al. The role of focal-adhesion kinase in cancer - a new therapeutic opportunity. Nature Rev. Cancer 5, 505–515 (2005).

    Article  CAS  Google Scholar 

  47. Miller, N. L., Lawson, C., Chen, X. L., Lim, S. T. & Schlaepfer, D. D. Rgnef (p190RhoGEF) knockout inhibits RhoA activity, focal adhesion establishment, and cell motility downstream of integrins. PLoS ONE 7, e37830 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Miller, N. L. et al. A non-canonical role for Rgnef in promoting integrin-stimulated focal adhesion kinase activation. J. Cell Sci. 126, 5074–5085 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Yu, H. G. et al. p190RhoGEF (Rgnef) promotes colon carcinoma tumor progression via interaction with focal adhesion kinase. Cancer Res. 71, 360–370 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lawson, C. et al. FAK promotes recruitment of talin to nascent adhesions to control cell motility. J. Cell Biol. 196, 223–232 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Barbero, S. et al. Caspase 8 association with the focal adhesion complex promotes tumor cell migration and metastasis. Cancer Res. 69, 3755–3763 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tomar, A., Lawson, C., Ghassemian, M. & Schlaepfer, D. D. Cortactin as a target for FAK in the regulation of focal adhesion dynamics. PLoS ONE 7, e44041 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Eke, I. et al. β1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J. Clin. Invest. 122, 1529–1540 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chan, K. T., Cortesio, C. L. & Huttenlocher, A. FAK alters invadopodia and focal adhesion composition and dynamics to regulate breast cancer invasion. J. Cell Biol. 185, 357–370 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Serrels, B. et al. Focal adhesion kinase controls actin assembly via a FERM-mediated interaction with the Arp2/3 complex. Nature Cell Biol. 9, 1046–1056 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Tang, H. et al. Loss of Scar/WAVE complex promotes N WASP- and FAK-dependent invasion. Curr. Biol. 23, 107–117 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Mitra, S. K., Lim, S. T., Chi, A. & Schlaepfer, D. D. Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model. Oncogene 25, 4429–4440 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, Y. & McNiven, M. A. Invasive matrix degradation at focal adhesions occurs via protease recruitment by a FAK p130Cas complex. J. Cell Biol. 196, 375–385 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen, J. S. et al. Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP 9 in liver cancer. Carcinogenesis 34, 10–19 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Lu, H. et al. KLF8 and FAK cooperatively enrich the active MMP14 on the cell surface required for the metastatic progression of breast cancer. Oncogene 33, 2909–2917 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Cicchini, C. et al. TGFβ-induced EMT requires focal adhesion kinase (FAK) signaling. Exp. Cell Res. 314, 143–152 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Avizienyte, E. et al. Src-induced de regulation of E cadherin in colon cancer cells requires integrin signalling. Nature Cell Biol. 4, 632–638 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Canel, M. et al. Quantitative in vivo imaging of the effects of inhibiting integrin signaling via Src and FAK on cancer cell movement: effects on E cadherin dynamics. Cancer Res. 70, 9413–9422 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lane, D., Goncharenko-Khaider, N., Rancourt, C. & Piche, A. Ovarian cancer ascites protects from TRAIL-induced cell death through alphavbeta5 integrin-mediated focal adhesion kinase and Akt activation. Oncogene 29, 3519–3531 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Kang, Y. et al. Role of focal adhesion kinase in regulating YB 1 mediated paclitaxel resistance in ovarian cancer. J. Natl Cancer Inst. 105, 1485–1495 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zheng, Y. et al. Protein tyrosine kinase 6 protects cells from anoikis by directly phosphorylating focal adhesion kinase and activating AKT. Oncogene 32, 4304–4312 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Bae, Y. H. et al. A FAK-Cas-Rac-Lamellipodin Signaling Module Transduces Extracellular Matrix Stiffness into Mechanosensitive Cell Cycling. Sci. Signal 7, ra57 (2014).

    PubMed  PubMed Central  Google Scholar 

  68. Lim, S. T. et al. Knock in mutation reveals an essential role for focal adhesion kinase activity in blood vessel morphogenesis and cell motility-polarity but not cell proliferation. J. Biol. Chem. 285, 21526–21536 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chen, X. L. et al. VEGF-induced vascular permeability is mediated by FAK. Dev. Cell 22, 146–157 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shibue, T. & Weinberg, R. A. Integrin β1 focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc. Natl Acad. Sci. USA 106, 10290–10295 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ashton, G. H. et al. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c Myc signaling. Dev. Cell 19, 259–269 (2010). This study shows that FAK is essential for WNT–MYC-mediated regeneration of the intestinal epithelium and provides a novel pathway by which FAK promotes transformation of APC-deficient epithelial cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Owen, K. A., Abshire, M. Y., Tilghman, R. W., Casanova, J. E. & Bouton, A. H. FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing. PLoS ONE 6, e23123 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nagy, T. et al. Mammary epithelial-specific deletion of the focal adhesion kinase gene leads to severe lobulo-alveolar hypoplasia and secretory immaturity of the murine mammary gland. J. Biol. Chem. 282, 31766–31776 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Luo, S. W. et al. Regulation of heterochromatin remodelling and myogenin expression during muscle differentiation by FAK interaction with MBD2. EMBO J. 28, 2568–2582 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lim, S. T. et al. Nuclear-localized focal adhesion kinase regulates inflammatory VCAM 1 expression. J. Cell Biol. 197, 907–919 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhao, X., Peng, X., Sun, S., Park, A. Y. & Guan, J. L. Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development. J. Cell Biol. 189, 955–965 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Graham, K., Moran-Jones, K., Sansom, O. J., Brunton, V. G. & Frame, M. C. FAK deletion promotes p53 mediated induction of p21, DNA-damage responses and radio-resistance in advanced squamous cancer cells. PLoS ONE 6, e27806 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tavora, B. et al. Endothelial-cell FAK targeting sensitises tumours to DNA-damaging therapy. Nature http://dx.doi.org/10.1038/nature13541 (2014).

  79. Walsh, C. et al. Oral delivery of PND 1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer Biol. Ther. 9, 778–790 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Joshi, I. et al. Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre B cells and progression to acute lymphoblastic leukemia. Nature Immunol. 15, 294–304 (2014).

    Article  CAS  Google Scholar 

  81. Braren, R. et al. Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation. J. Cell Biol. 172, 151–162 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schmidt, T. T. et al. Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities. Am. J. Physiol. Lung Cell. Mol. Physiol. 305, L291–L300 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Shen, T. L. et al. Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J. Cell Biol. 169, 941–952 (2005). References 68 and 83 created FAK-KD knock-in mouse models to test the importance of FAK enzymatic activity during development. FAK-KD is embryonically lethal owing to defective blood vessel formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Corsi, J. M. et al. Autophosphorylation-independent and -dependent functions of focal adhesion kinase during development. J. Biol. Chem. 284, 34769–34776 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Infusino, G. A. & Jacobson, J. R. Endothelial FAK as a therapeutic target in disease. Microvasc. Res. 83, 89–96 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Angelucci, A. & Bologna, M. Targeting vascular cell migration as a strategy for blocking angiogenesis: the central role of focal adhesion protein tyrosine kinase family. Curr. Pharm. Des. 13, 2129–2145 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Lu, C. et al. Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma. Cancer Res. 67, 1757–1768 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Jean, C. et al. Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function. J. Cell Biol. 204, 247–263 (2014). This study shows that pharmacological inhibition of FAK or endothelial-specific expression of FAK-KD prevents extravasation and spontaneous tumour spread by enhancing endothelial vessel barrier function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cabrita, M. A. et al. Focal adhesion kinase inhibitors are potent anti-angiogenic agents. Mol. Oncol. 5, 517–526 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dave, J. M., Kang, H., Abbey, C. A., Maxwell, S. A. & Bayless, K. J. Proteomic profiling of endothelial invasion revealed receptor for activated C kinase 1 (RACK1) complexed with vimentin to regulate focal adhesion kinase (FAK). J. Biol. Chem. 288, 30720–30733 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lee, J., Borboa, A. K., Chun, H. B., Baird, A. & Eliceiri, B. P. Conditional deletion of the focal adhesion kinase FAK alters remodeling of the blood-brain barrier in glioma. Cancer Res. 70, 10131–10140 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Tavora, B. et al. Endothelial FAK is required for tumour angiogenesis. EMBO Mol. Med. 2, 516–528 (2010). This report provides genetic evidence for a causative role for EC FAK expression in promoting tumour angiogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kostourou, V. et al. FAK-heterozygous mice display enhanced tumour angiogenesis. Nature Commun. 4, 2020 (2013).

    Article  CAS  Google Scholar 

  94. Schultze, A. & Fiedler, W. Therapeutic potential and limitations of new FAK inhibitors in the treatment of cancer. Expert Opin. Investig. Drugs 19, 777–788 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Halder, J. et al. Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. Cancer Res. 67, 10976–10983 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Bagi, C. M. 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. 8, 856–865 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Arnold, K. M., Goeckeler, Z. M. & Wysolmerski, R. B. Loss of focal adhesion kinase enhances endothelial barrier function and increases focal adhesions. Microcirculation 20, 637–649 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Schober, M. et al. Focal adhesion kinase modulates tension signaling to control actin and focal adhesion dynamics. J. Cell Biol. 176, 667–680 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hiratsuka, S. et al. Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E selectin up regulation. Proc. Natl Acad. Sci. USA 108, 3725–3730 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kasorn, A. et al. Focal adhesion kinase regulates pathogen-killing capability and life span of neutrophils via mediating both adhesion-dependent and -independent cellular signals. J. Immunol. 183, 1032–1043 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Owen, K. A. et al. Regulation of lamellipodial persistence, adhesion turnover, and motility in macrophages by focal adhesion kinase. J. Cell Biol. 179, 1275–1287 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Stokes, J. B. et al. Inhibition of focal adhesion kinase by PF 562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol. Cancer Ther. 10, 2135–2145 (2011). This study shows that FAK inhibition blocks pancreatic tumour proliferation, either directly, by inhibiting tumour cell proliferation, or indirectly, by impairing the recruitment and/or proliferation of stromal cells to the tumour microenvironment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wendt, M. K. & Schiemann, W. P. Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-β signaling and metastasis. Breast Cancer Res. 11, R68 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Lu, J. et al. Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion. Exp. Hematol. 40, 307–317 e3 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Vemula, S. et al. Essential role for focal adhesion kinase in regulating stress hematopoiesis. Blood 116, 4103–4115 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hitchcock, I. S. et al. Roles of focal adhesion kinase (FAK) in megakaryopoiesis and platelet function: studies using a megakaryocyte lineage specific FAK knockout. Blood 111, 596–604 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Roh, M. E., Cosgrove, M., Gorski, K. & Hitchcock, I. S. Off-targets effects underlie the inhibitory effect of FAK inhibitors on platelet activation: studies using Fak-deficient mice. J. Thromb. Haemost. 11, 1776–1778 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Barker, H. E., Bird, D., Lang, G. & Erler, J. T. Tumor-secreted LOXL2 activates fibroblasts through FAK signaling. Mol. Cancer Res. 11, 1425–1436 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Lagares, D. et al. Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation. Arthritis Rheum. 64, 1653–1664 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Greenberg, R. S. et al. FAK-dependent regulation of myofibroblast differentiation. FASEB J. 20, 1006–1008 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Mitra, S. K. et al. Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors. Oncogene 25, 5969–5984 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Despeaux, M. et al. Critical features of FAK-expressing AML bone marrow microenvironment through leukemia stem cell hijacking of mesenchymal stromal cells. Leukemia 25, 1789–1793 (2011). This study supports the idea that the ability of bone marrow mesenchymal stromal cells to organize a pro-tumoural niche (favouring quiescence and resistance of haematopoietic stem cells) is dependent on FAK expression within acute myeloid leukaemia.

    Article  CAS  PubMed  Google Scholar 

  113. Parsons, J. T., Slack-Davis, J., Tilghman, R. & Roberts, W. G. Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin. Cancer Res. 14, 627–632 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. McLean, G. W. et al. Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. Genes Dev. 18, 2998–3003 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Slack-Davis, J. K., Hershey, E. D., Theodorescu, D., Frierson, H. F. & Parsons, J. T. Differential requirement for focal adhesion kinase signaling in cancer progression in the transgenic adenocarcinoma of mouse prostate model. Mol. Cancer Ther. 8, 2470–2477 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bolos, V., Gasent, J. M., Lopez-Tarruella, S. & Grande, E. The dual kinase complex FAK-Src as a promising therapeutic target in cancer. Onco Targets Ther. 3, 83–97 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Serrels, A. et al. The role of focal adhesion kinase catalytic activity on the proliferation and migration of squamous cell carcinoma cells. Int. J. Cancer 131, 287–297 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Lu, H. et al. IGFBP2/FAK pathway is causally associated with dasatinib resistance in non-small cell lung cancer cells. Mol. Cancer Ther. 12, 2864–2873 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Shi, Q. et al. A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth. Mol. Carcinog. 46, 488–496 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Slack-Davis, J. K. et al. Cellular characterization of a novel focal adhesion kinase inhibitor. J. Biol. Chem. 282, 14845–14852 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Roberts, W. G. et al. Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF 562,271. Cancer Res. 68, 1935–1944 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Tanjoni, I. et al. PND 1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer Biol. Ther. 9, 764–777 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Lietha, D. & Eck, M. J. Crystal structures of the FAK kinase in complex with TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation. PLoS ONE 3, e3800 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Shapiro, I. M. et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci. Transl Med. 6, 237ra68 (2014). This study shows that mesothelioma cells with low expression of the tumour suppressor Merlin are very sensitive to pharmacological FAK inhibition, and it is therefore the first to identify a potential biomarker for patient stratification for chemotherapy.

    PubMed  PubMed Central  Google Scholar 

  126. Shah, N. R. et al. Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer. Gynecol. Oncol. 134, 104–111 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Tomita, N. et al. Structure-based discovery of cellular-active allosteric inhibitors of FAK. Bioorg. Med. Chem. Lett. 23, 1779–1785 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Heinrich, T. et al. Fragment-based discovery of new highly substituted 1H pyrrolo[2,3 b]- and 3H imidazolo[4,5 b]-pyridines as focal adhesion kinase inhibitors. J. Med. Chem. 56, 1160–1170 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Golubovskaya, V. M. et al. A small molecule focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2 hydroxyethyl)-3, 5, 7 triaza-1 azoniatricyclo [3.3.1.1(3,7)]decane; bromide effectively inhibits FAK autophosphorylation activity and decreases cancer cell viability, clonogenicity and tumor growth in vivo. Carcinogenesis 33, 1004–1013 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Cance, W. G., Kurenova, E., Marlowe, T. & Golubovskaya, V. Disrupting the scaffold to improve focal adhesion kinase-targeted cancer therapeutics. Sci. Signal 6, e10 (2013).

    Article  CAS  Google Scholar 

  131. Golubovskaya, V. M. et al. Disruption of focal adhesion kinase and p53 interaction with small molecule compound R2 reactivated p53 and blocked tumor growth. BMC Cancer 13, 342 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Infante, J. R. et al. Safety, pharmacokinetic, and pharmacodynamic phase I dose-escalation trial of PF 00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors. J. Clin. Oncol. 30, 1527–1533 (2012). This is the first clinical trial report of a completed Phase I study with an ATP-competitive FAK kinase inhibitor, showing that it is safe and well-tolerated.

    Article  CAS  PubMed  Google Scholar 

  133. Konstantinidou, G. et al. RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov. 3, 444–457 (2013). This study shows that RHOA–FAK signalling drives lung cancer tumour progression upon loss of CDKN2A and expression of mutant KRAS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Crompton, B. D. et al. High-throughput tyrosine kinase activity profiling identifies FAK as a candidate therapeutic target in Ewing sarcoma. Cancer Res. 73, 2873–2883 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Tancioni, I. et al. FAK inhibition disrupts a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth. Mol. Cancer Ther. http://dx.doi.org/10.1158/1535-7163.MCT-13-1063 (2014).

  136. Lulo, J., Yuzawa, S. & Schlessinger, J. Crystal structures of free and ligand-bound focal adhesion targeting domain of Pyk2. Biochem. Biophys. Res. Commun. 383, 347–352 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Kuang, B. H. et al. Proline-rich tyrosine kinase 2 and its phosphorylated form pY881 are novel prognostic markers for non-small-cell lung cancer progression and patients' overall survival. Br. J. Cancer 109, 1252–1263 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Loftus, J. C. et al. miRNA expression profiling in migrating glioblastoma cells: regulation of cell migration and invasion by miR 23b via targeting of Pyk2. PLoS ONE 7, e39818 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Fan, H. & Guan, J. L. Compensatory function of Pyk2 protein in the promotion of focal adhesion kinase (FAK)-null mammary cancer stem cell tumorigenicity and metastatic activity. J. Biol. Chem. 286, 18573–18582 (2011). This study shows how PYK2 compensates for FAK loss in mouse tumour models and controls MaCSC renewal, tumour growth and metastasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Goñi, G. M. et al. Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes. Proc. Natl Acad. Sci. USA http://dx.doi.org/10.1073/pnas.1317022111 (2014).

  141. 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).

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Reproductive Medicine, University of California San Diego, Moores Cancer Center, 3855 Health Sciences Dr., MC0803, La Jolla, 92093, California, USA

    Florian J. Sulzmaier, Christine Jean & David D. Schlaepfer

Authors
  1. Florian J. Sulzmaier
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Christine Jean
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. David D. Schlaepfer
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to David D. Schlaepfer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Glossary

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.

Invadopodia

Specialized membrane protrusions (also known as an invasive pseudopodia) in which active extracellular matrix degradation takes place.

ARP2/3

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.

Anoikis

Cell death (apoptosis) that is induced by the loss of cell matrix adhesion and a physiological mechanism to prevent cell displacement.

Mammospheres

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3792

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer