Advertisement

FAK as a Target for Therapy in Head and Neck Cancer

  • Nassim Khosravi
  • Heath Skinner
  • John Heymach
Chapter
Part of the Current Cancer Research book series (CUCR)

Abstract

Despite decades of concerted effort, treatments for head and neck squamous cell carcinoma (HNSCC) have remained largely unchanged, with tumors typically managed using a combination of surgery, radiotherapy, and cytotoxic chemotherapy. Suboptimal efficacy and often severe toxicities associated with some of these treatments have encouraged development of targeted therapies that may overcome these limitations. One promising avenue of therapeutic development in HNSCC in particular has addressed integrins and integrin-mediated signaling, which mediates interactions between the tumor and the extracellular matrix (ECM) and can potentially be targeted by inhibition of the integrin-associated focal adhesion kinase (FAK). This chapter summarizes FAK structure-function relationships and how FAK impacts multiple cellular processes relevant to HNSCC, including survival and invasion. We will discuss the development of targeted FAK inhibitors, and combinatorial strategies incorporating FAK inhibition, with comparisons between human papillomavirus (HPV)-positive and HPV-negative HNSCC.

Keywords

Focal adhesion kinase Cancer Chemotherapy Radiation 

Bibliography

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic – a review of epidemiology, biology, virus detection and issues in management. Lancet Oncol. 2010;11(8):781–9.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Integrins. 2002. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26867/.
  5. 5.
    Kanner SB, Reynolds AB, Parsons JT. Immunoaffinity purification of tyrosine-phosphorylated cellular proteins. J Immunol Methods. 1989;120(1):115–24.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Mitra SK, Schlaepfer DD. Integrin-regulated FAK–Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006;18(5):516–23.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Yoon H, Dehart JP, Murphy JM, Lim S-TS. Understanding the roles of FAK in Cancer: inhibitors, genetic models, and new insights. J Histochem Cytochem. 2015;63(2):114–28.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Golubovskaya VM. Targeting FAK in human cancer: from finding to first clinical trials. Front Biosci. 2014;19:687–706.CrossRefGoogle Scholar
  9. 9.
    Abedi H, Zachary I. Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem. 1997;272(24):15442–51.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Laurent-Puig P, Lievre A, Blons H. Mutations and response to epidermal growth factor receptor inhibitors. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15(4):1133–9.CrossRefGoogle Scholar
  11. 11.
    Saito Y, Mori S, Yokote K, Kanzaki T, Saito Y, Morisaki N. Phosphatidylinositol 3-kinase activity is required for the activation process of focal adhesion kinase by platelet-derived growth factor. Biochem Biophys Res Commun. 1996;224(1):23–6.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Danilkovitch A, Leonard EJ. Kinases involved in MSP/RON signaling. J Leukoc Biol. 1999;65(3):345–8.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Aoto H, Sasaki H, Ishino M, Sasaki T. Nuclear translocation of cell adhesion kinase beta/proline-rich tyrosine kinase 2. Cell Struct Funct. 2002;27(1):47–61.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Lim S-T, Chen XL, Lim Y, Hanson DA, Vo T-T, Howerton K, et al. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell. 2008;29(1):9–22.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Serrels A, Lund T, Serrels B, Byron A, McPherson RC, von Kriegsheim A, et al. Nuclear FAK controls chemokine transcription, tregs, and evasion of anti-tumor immunity. Cell. 2015;163(1):160–73.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Polte TR, Hanks SK. Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas. Proc Natl Acad Sci U S A. 1995;92(23):10678–82.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Law SF, Estojak J, Wang B, Mysliwiec T, Kruh G, Golemis EA. Human enhancer of filamentation 1, a novel p130cas-like docking protein, associates with focal adhesion kinase and induces pseudohyphal growth in Saccharomyces cerevisiae. Mol Cell Biol. 1996;16(7):3327–37.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Hildebrand JD, Taylor JM, Parsons JT. An SH3 domain-containing GTPase-activating protein for rho and Cdc42 associates with focal adhesion kinase. Mol Cell Biol. 1996;16(6):3169–78.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Wu X, Gan B, Yoo Y, Guan J-L. FAK-mediated src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation. Dev Cell. 2005;9(2):185–96.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Hildebrand JD, Schaller MD, Parsons JT. Paxillin, a tyrosine phosphorylated focal adhesion-associated protein binds to the carboxyl terminal domain of focal adhesion kinase. Mol Biol Cell. 1995;6(6):637–47.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Chen HC, Appeddu PA, Parsons JT, Hildebrand JD, Schaller MD, Guan JL. Interaction of focal adhesion kinase with cytoskeletal protein Talin. J Biol Chem. 1995;270(28):16995–9.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Longhurst CM, Jennings LK. Integrin-mediated signal transduction. Cell Mol Life Sci CMLS. 1998;54(6):514–26.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Wang P, Ballestrem C, Streuli CH. The C terminus of Talin links integrins to cell cycle progression. J Cell Biol. 2011;195(3):499–513.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Lawson C, Lim S-T, Uryu S, Chen XL, Calderwood DA, Schlaepfer DD. FAK promotes recruitment of Talin to nascent adhesions to control cell motility. J Cell Biol 2012;196(3):223–232.Google Scholar
  25. 25.
    Zhang X, Chattopadhyay A, Ji Q, Owen JD, Ruest PJ, Carpenter G, et al. Focal adhesion kinase promotes phospholipase C-γ1 activity. Proc Natl Acad Sci U S A. 1999;96(16):9021–6.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Chen H-C, Appeddu PA, Isoda H, Guan J-L. Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. J Biol Chem. 1996;271(42):26329–34.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Calalb MB, Polte TR, Hanks SK. 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;15(2):954–63.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Li L, Okura M, Imamoto A. Focal adhesions require catalytic activity of Src family kinases to mediate integrin-matrix adhesion. Mol Cell Biol. 2002;22(4):1203–17.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Westhoff MA, Serrels B, Fincham VJ, Frame MC, Carragher NO. Src-mediated phosphorylation of focal adhesion kinase couples actin and adhesion dynamics to survival signaling. Mol Cell Biol. 2004;24(18):8113–33.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Abu-Ghazaleh R, Kabir J, Jia H, Lobo M, Zachary I. Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells. Biochem J. 2001;360(Pt 1):255–64.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Sridhar SC, Miranti CK. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-met receptor and Src kinases. Oncogene. 2006;25(16):2367–78.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Arold ST, Hoellerer MK, Noble MEM. The structural basis of localization and signaling by the focal adhesion targeting domain. Structure. 2002; 10(3):319–27. London, England: 1993.Google Scholar
  33. 33.
    Flinder LI, Timofeeva OA, Rosseland CM, Wierød L, Huitfeldt HS, Skarpen E. EGF-induced ERK-activation downstream of FAK requires rac1-NADPH oxidase. J Cell Physiol. 2011;226(9):2267–78.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Sieg DJ, Ilić D, Jones KC, Damsky CH, Hunter T, Schlaepfer DD. Pyk2 and Src-family protein-tyrosine kinases compensate for the loss of FAK in fibronectin-stimulated signaling events but Pyk2 does not fully function to enhance FAK-cell migration. EMBO J. 1998;17(20):5933–47.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Yue Y, Li Z-N, Fang Q-G, Zhang X, Yang L-L, Sun C-F, et al. The role of Pyk2 in the CCR7-mediated regulation of metastasis and viability in squamous cell carcinoma of the head and neck cells in vivo and in vitro. Oncol Rep. 2015;34(6):3280–7.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta BBA – Mol Cell Biol Lipids. 2013;1833(12):3481–98.CrossRefGoogle Scholar
  37. 37.
    Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 1994;124(4):619–26.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T. Anti-apoptotic role of focal adhesion kinase (FAK) induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of fak in a human leukemic cell line, HL-60. J Biol Chem. 2000;275(21):16309–15.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Golubovskaya VM, Huang G, Ho B, Yemma M, Morrison CD, Lee J, Eliceiri BP, Cance WG. Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide. Mol Cancer Ther. 2013;12(2):162–72. https://doi.org/10.1158/1535-7163. MCT-12-0701. Epub 2012 Dec 12. PubMed PMID: 23243059; PubMed Central PMCID: PMC3570595.Google Scholar
  40. 40.
    Golubovskaya VM, Finch R, Kweh F, Massoll NA, Campbell-Thompson M, Wallace MR, et al. p53 regulates FAK expression in human tumor cells. Mol Carcinog. 2008;47(5):373–82.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Golubovskaya VM, Conway-Dorsey K, Edmiston SN, Tse C-K, Lark AA, Livasy CA, et al. FAK overexpression and p53 mutations are highly correlated in human breast cancer. Int J Cancer. 2009;125(7):1735–8.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Schlaepfer DD, Jones KC, Hunter T. Multiple Grb2-mediated integrin-stimulated signaling pathways to ERK2/mitogen-activated protein kinase: summation of both c-Src- and focal adhesion kinase-initiated tyrosine phosphorylation events. Mol Cell Biol. 1998;18(5):2571–85.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Xia H, Nho RS, Kahm J, Kleidon J, Henke CA. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem. 2004;279(31):33024–34.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Kamarajan P, Bunek J, Lin Y, Nunez G, Kapila YL. Receptor-interacting protein shuttles between cell death and survival signaling pathways. Mol Biol Cell. 2010;21(3):481–8.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Tong L, Tergaonkar V. Rho protein GTPases and their interactions with NFκB: crossroads of inflammation and matrix biology. Biosci Rep. 2014;34(3):e00115. https://doi.org/10.1042/BSR20140021. Review. PubMed PMID: 24877606; PubMed Central PMCID: PMC4069681.Google Scholar
  46. 46.
    You D, Xin J, Volk A, Wei W, Schmidt R, Scurti G, et al. FAK mediates a compensatory survival signal parallel to PI3K-AKT in PTEN-null T-ALL cells. Cell Rep. 2015;10(12):2055–68.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    O’Neill GM, Seo S, Serebriiskii IG, Lessin SR, Golemis EA. A new central scaffold for metastasis: parsing HEF1/Cas-L/NEDD9. Cancer Res. 2007;67(19):8975–9.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Nikonova AS, Gaponova AV, Kudinov AE, Golemis EA. CAS proteins in health and disease: an update. IUBMB Life. 2014;66(6):387–95.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    O’Neill GM, Fashena SJ, Golemis EA. Integrin signalling: a new cas(t) of characters enters the stage. Trends Cell Biol. 2000;10(3):111–9.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Lucas JT, Salimath BP, Slomiany MG, Rosenzweig SA. Regulation of invasive behavior by vascular endothelial growth factor is HEF1-dependent. Oncogene. 2010;29(31):4449–59.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Schaller M. Paxillin: a focal adhesion-associated adaptor protein. Oncogene. 2001;20(44):6459–72.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Lim Y, Lim S-T, Tomar A, Gardel M, Bernard-Trifilo JA, Chen XL, et al. PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility. J Cell Biol. 2008;180(1):187–203.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Sieg DJ, Hauck CR, Schlaepfer DD. Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci. 1999;112(Pt 16):2677–91.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Tilghman R, Parsons JT. Focal adhesion kinase as a regulator of cell tension in the progression of cancer. Semin Cancer Biol. 2008;18(1):45–52.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Ammer A, Weed S. Cortactin branches out: roles in regulating protrusive actin dynamics. Cell Motil Cytoskelet. 2008;65(9):687–707.CrossRefGoogle Scholar
  56. 56.
    Segarra M, Vilardell C, Matsumoto K, Esparza J, Lozano E, Serra-Pages C, et al. Dual function of focal adhesion kinase in regulating integrin-induced MMP-2 and MMP-9 release by human T lymphoid cells. FASEB J Off Publ Fed Am Soc Exp Biol. 2005;19(13):1875–7.Google Scholar
  57. 57.
    Kwiatkowska A, Kijewska M, Lipko M, Hibner U, Kaminska B. Downregulation of Akt and FAK phosphorylation reduces invasion of glioblastoma cells by impairment of MT1-MMP shuttling to lamellipodia and downregulates MMPs expression. Biochim Biophys Acta. 2011;1813(5):655–67.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Pan Y-R, Chen C-L, Chen H-C. FAK is required for the assembly of podosome rosettes. J Cell Biol. 2011;195(1):113–29.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Li X-Y, Zhou X, Rowe RG, Hu Y, Schlaepfer DD, Ilić D, et al. Snail1 controls epithelial–mesenchymal lineage commitment in focal adhesion kinase–null embryonic cells. J Cell Biol. 2011;195(5):729–38.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Cicchini C, Laudadio I, Citarella F, Corazzari M, Steindler C, Conigliaro A, et al. TGFbeta-induced EMT requires focal adhesion kinase (FAK) signaling. Exp Cell Res. 2008;314(1):143–52.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Cicchini C, Laudadio I, Citarella F, Corazzari M, Steindler C, Conigliaro A, et al. TGFβ-induced EMT requires focal adhesion kinase (FAK) signaling. Exp Cell Res. 2008;314(1):143–52.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Saito D, Kyakumoto S, Chosa N, Ibi M, Takahashi N, Okubo N, et al. Transforming growth factor-β1 induces epithelial–mesenchymal transition and integrin α3β1-mediated cell migration of HSC-4 human squamous cell carcinoma cells through Slug. J Biochem (Tokyo). 2013;153(3):303–15.CrossRefGoogle Scholar
  63. 63.
    Avizienyte E, Wyke AW, Jones RJ, McLean GW, Westhoff MA, Brunton VG, et al. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat Cell Biol. 2002;4(8):632–8.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Taliaferro-Smith L, Oberlick E, Liu T, McGlothen T, Alcaide T, Tobin R, et al. FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells. Oncotarget. 2015;6(7):4757–72.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Rodrigo JP, Dominguez F, Suárez V, Canel M, Secades P, Chiara MD. Focal adhesion kinase and E-cadherin as markers for nodal metastasis in laryngeal cancer. Arch Otolaryngol Head Neck Surg. 2007;133(2):145–50.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    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. 2013;288(5):3322–33.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Te Boekhorst V, Preziosi L, Friedl P. Plasticity of cell migration in vivo and in silico. Annu Rev Cell Dev Biol. 2016;32:491–526.CrossRefGoogle Scholar
  68. 68.
    Sanz-Moreno V, Gadea G, Ahn J, Paterson H, Marra P, Pinner S, et al. Rac activation and inactivation control plasticity of tumor cell movement. Cell. 2008;135(3):510–23.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Ahn J, Sanz-Moreno V, Marshall CJ. The metastasis gene NEDD9 product acts through integrin β3 and Src to promote mesenchymal motility and inhibit amoeboid motility. J Cell Sci. 2012;125(Pt 7):1814–26.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Ilić D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature. 1995;377(6549):539–44.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Shen T-L, Park AY-J, Alcaraz A, Peng X, Jang I, Koni P, 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. 2005;169(6):941–52.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Zhao X, Peng X, Sun S, Park AYJ, 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. 2010;189(6):955–65.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Tavora B, Batista S, Reynolds LE, Jadeja S, Robinson S, Kostourou V, et al. Endothelial FAK is required for tumour angiogenesis. EMBO Mol Med. 2010;2(12):516–28.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Mitra SK, Mikolon D, Molina JE, Hsia DA, Hanson DA, Chi A, et al. Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors. Oncogene. 2006;25(44):5969–84.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Kostourou V, Lechertier T, Reynolds LE, Lees DM, Baker M, Jones DT, et al. FAK-heterozygous mice display enhanced tumour angiogenesis. Nat Commun. 2013;4:2020: 1–11.Google Scholar
  76. 76.
    Weis SM, Lim S-T, Lutu-Fuga KM, Barnes LA, Chen XL, Göthert JR, et al. Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK. J Cell Biol. 2008;181(1):43–50.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Luo M, Fan H, Nagy T, Wei H, Wang C, Liu S, et al. Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells. Cancer Res. 2009;69(2):466–74.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    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. 2011;286(21):18573–82.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Luo M, Zhao X, Chen S, Liu S, Wicha MS, Guan J-L. Distinct FAK activities determine progenitor and mammary stem cell characteristics. Cancer Res. 2013;73(17):5591–602.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Schober M, Fuchs E. Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling. Proc Natl Acad Sci U S A. 2011;108(26):10544–9.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Kobayashi K, Takahashi H, Inoue A, Harada H, Toshimori S, Kobayashi Y, et al. Oct-3/4 promotes migration and invasion of glioblastoma cells. J Cell Biochem. 2012;113(2):508–17.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Lin Y-L, Han Z-B, Xiong F-Y, Tian L-Y, Wu X-J, Xue S-W, et al. Malignant transformation of 293 cells induced by ectopic expression of human Nanog. Mol Cell Biochem. 2011;351(1–2):109–16.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Ho B, Olson G, Figel S, Gelman I, Cance WG, Golubovskaya VM. Nanog increases focal adhesion kinase (FAK) promoter activity and expression and directly binds to FAK protein to be phosphorylated. J Biol Chem. 2012;287(22):18656–73.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333–9.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Skinner HD, Giri U, Yang L, Woo SH, Story MD, Pickering CR, Byers LA, Williams MD, El-Naggar A, Wang J, Diao L, Shen L, Fan YH, Molkentine DP, Beadle BM, Meyn RE, Myers JN, Heymach JV. Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer. Clin Cancer Res. 2016;22(18):4643–50. https://doi.org/10.1158/1078-0432.CCR-15-2785. Epub 2016 Apr 1. PubMed PMID: 27036135; PubMed Central PMCID: PMC5061056.Google Scholar
  86. 86.
    Recher C, Ysebaert L, Beyne-Rauzy O, Mas VM-D, Ruidavets J-B, Cariven P, et al. Expression of focal adhesion kinase in acute myeloid leukemia is associated with enhanced blast migration, increased cellularity, and poor prognosis. Cancer Res. 2004;64(9):3191–7.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Charpin C, Secq V, Giusiano S, Carpentier S, Andrac L, Lavaut M-N, et al. A signature predictive of disease outcome in breast carcinomas, identified by quantitative immunocytochemical assays. Int J Cancer. 2009;124(9):2124–34.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Schmitz KJ, Grabellus F, Callies R, Otterbach F, Wohlschlaeger J, Levkau B, et al. High expression of focal adhesion kinase (p125FAK) in node-negative breast cancer is related to overexpression of HER-2/neu and activated Akt kinase but does not predict outcome. Breast Cancer Res. 2005;7:R194.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Canel M, Secades P, Rodrigo J-P, Cabanillas R, Herrero A, Suarez C, et al. Overexpression of focal adhesion kinase in head and neck squamous cell carcinoma is independent of fak gene copy number. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12(11 Pt 1):3272–9.CrossRefGoogle Scholar
  90. 90.
    Omura G, Ando M, Saito Y, Kobayashi K, Yoshida M, Ebihara Y, et al. Association of the upregulated expression of focal adhesion kinase with poor prognosis and tumor dissemination in hypopharyngeal cancer. Head Neck. 2016;38(8):1164–9.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Lee BY, Timpson P, Horvath LG, Daly RJ. FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther. 2015;146:132–49.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Liu W, Bloom DA, Cance WG, Kurenova EV, Golubovskaya VM, Hochwald SN. FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells. Carcinogenesis. 2008;29(6):1096–107.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Golubovskaya VM, Ho B, Zheng M, Magis A, Ostrov D, Cance WG. Mitoxantrone targets the ATP-binding site of FAK, binds the FAK kinase domain and decreases FAK, Pyk-2, c-Src, and IGF-1R in vitro kinase activities. Anti Cancer Agents Med Chem. 2013;13(4):546–54.CrossRefGoogle Scholar
  94. 94.
    Wendt MK, Schiemann WP. Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-beta signaling and metastasis. Breast Cancer Res BCR. 2009;11(5):R68.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Kang Y, Hu W, Ivan C, Dalton HJ, Miyake T, Pecot CV, et al. Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer. J Natl Cancer Inst. 2013;105(19):1485–95.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Hallur G, Tamizharasan N, Sulochana SP, Saini NK, Zainuddin M, Mullangi R. LC-ESI-MS/MS determination of defactinib, a novel FAK inhibitor in mice plasma and its application to a pharmacokinetic study in mice. J Pharm Biomed Anal. 2017;149:358–64.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Walsh C, Tanjoni I, Uryu S, Tomar A, Nam J-O, Luo H, 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. 2010;9(10):778–90.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Zhang J, He D-H, Zajac-Kaye M, Hochwald SN. A small molecule FAK kinase inhibitor, GSK2256098, inhibits growth and survival of pancreatic ductal adenocarcinoma cells. Cell Cycle Georget Tex. 2014;13(19):3143–9.CrossRefGoogle Scholar
  99. 99.
    Soria JC, Gan HK, Blagden SP, Plummer R, Arkenau HT, Ranson M, et al. A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors. Ann Oncol Off J Eur Soc Med Oncol. 2016;27(12):2268–74.CrossRefGoogle Scholar
  100. 100.
    O’Brien S, Golubovskaya VM, Conroy J, Liu S, Wang D, Liu B, et al. FAK inhibition with small molecule inhibitor Y15 decreases viability, clonogenicity, and cell attachment in thyroid cancer cell lines and synergizes with targeted therapeutics. Oncotarget. 2014;5(17):7945–59.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Kurenova EV, Hunt DL, He D, Magis AT, Ostrov DA, Cance WG. Small molecule chloropyramine hydrochloride (C4) targets the binding site of focal adhesion kinase and vascular endothelial growth factor receptor 3 and suppresses breast cancer growth in vivo. J Med Chem. 2009;52(15):4716–24.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Kurenova E, Ucar D, Liao J, Yemma M, Gogate P, Bshara W, et al. A FAK scaffold inhibitor disrupts FAK and VEGFR-3 signaling and blocks melanoma growth by targeting both tumor and endothelial cells. Cell Cycle Georget Tex. 2014;13(16):2542–53.CrossRefGoogle Scholar
  103. 103.
    Moen I, Gebre M, Alonso-Camino V, Chen D, Epstein D, McDonald DM. Anti-metastatic action of FAK inhibitor OXA-11 in combination with VEGFR-2 signaling blockade in pancreatic neuroendocrine tumors. Clin Exp Metastasis. 2015;32(8):799–817.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Ucar DA, Cox A, He D-H, Ostrov DA, Kurenova E, Hochwald SN. A novel small molecule inhibitor of FAK and IGF-1R protein interactions decreases growth of human esophageal carcinoma. Anti Cancer Agents Med Chem. 2011;11(7):629–37.CrossRefGoogle Scholar
  105. 105.
    Ucar DA, Kurenova E, Garrett TJ, Cance WG, Nyberg C, Cox A, et al. Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth. Cell Cycle Georget Tex. 2012;11(17):3250–9.CrossRefGoogle Scholar
  106. 106.
    Golubovskaya VM, Palma NL, Zheng M, Ho B, Magis A, Ostrov D, et al. A small-molecule inhibitor, 5′-O-tritylthymidine, targets FAK and Mdm-2 interaction, and blocks breast and colon tumorigenesis in vivo. Anti Cancer Agents Med Chem. 2013;13(4):532–45.CrossRefGoogle Scholar
  107. 107.
    Golubovskaya VM, Ho B, Zheng M, Magis A, Ostrov D, Morrison C, et al. Disruption of focal adhesion kinase and p53 interaction with small molecule compound R2 reactivated p53 and blocked tumor growth. BMC Cancer. 2013;13(1):342.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Aoudjit F, Vuori K. Integrin signaling in cancer cell survival and chemoresistance [internet]. Chemotherapy Research and Practice. 2012. Available from: https://www.hindawi.com/journals/cherp/2012/283181/.
  109. 109.
    Dragoj M, Milosevic Z, Bankovic J, Tanic N, Pesic M, Stankovic T. Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma. Cell Oncol Dordr. 2017;40(1):47–62.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Kolev VN, Tam WF, Wright QG, McDermott SP, Vidal CM, Shapiro IM, et al. Inhibition of FAK kinase activity preferentially targets cancer stem cells. Oncotarget. 2017;8(31):51733–47.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Halder J, Lin YG, Merritt WM, Spannuth WA, Nick AM, Honda T, et al. Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. Cancer Res. 2007;67(22):10976–83.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Heffler M, Golubovskaya VM, Dunn KMB, Cance W. Focal adhesion kinase autophosphorylation inhibition decreases colon cancer cell growth and enhances the efficacy of chemotherapy. Cancer Biol Ther. 2013;14(8):761–72.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Hochwald SN, Nyberg C, Zheng M, Zheng D, Wood C, Massoll NA, et al. A novel small molecule inhibitor of FAK decreases growth of human pancreatic cancer. Cell Cycle. 2009;8(15):2435–43.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Kurio N, Shimo T, Fukazawa T, Okui T, Hassan NMM, Honami T, et al. Anti-tumor effect of a novel FAK inhibitor TAE226 against human oral squamous cell carcinoma. Oral Oncol. 2012;48(11):1159–70.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Infante JR, Camidge DR, Mileshkin LR, Chen EX, Hicks RJ, Rischin D, 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. 2012;30(13):1527–33.Google Scholar
  116. 116.
    Haemmerle M, Bottsford-Miller J, Pradeep S, Taylor ML, Choi H-J, Hansen JM, et al. FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal. J Clin Invest. 2016;126(5):1885–96.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Sandfort V, Koch U, Cordes DN. Cell adhesion-mediated radioresistance revisited. Int J Radiat Biol. 2007;83(11–12):727–32.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Eke I, Deuse Y, Hehlgans S, Gurtner K, Krause M, Baumann M, et al. β1Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J Clin Invest. 2012;122(4):1529–40.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Eke I, Dickreuter E, Cordes N. Enhanced radiosensitivity of head and neck squamous cell carcinoma cells by β1 integrin inhibition. Radiother Oncol. 2012;104(2):235–42.Google Scholar
  120. 120.
    Dickreuter E, Eke I, Krause M, Borgmann K, van Vugt MA, Cordes N. Targeting of β1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells. Oncogene. 2016;35(11):1353–62.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Albert M, Schmidt M, Cordes N, Dörr W. Modulation of radiation-induced oral mucositis (mouse) by selective inhibition of β1 integrin. Radiother Oncol. 2012;104(2):230–4.Google Scholar
  122. 122.
    Ning S, Tian J, Marshall DJ, Knox SJ. Anti-alphav integrin monoclonal antibody intetumumab enhances the efficacy of radiation therapy and reduces metastasis of human cancer xenografts in nude rats. Cancer Res. 2010;70(19):7591–9.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Ning S, Nemeth JA, Hanson RL, Forsythe K, Knox SJ. Anti-integrin monoclonal antibody CNTO 95 enhances the therapeutic efficacy of fractionated radiation therapy in vivo. Mol Cancer Ther. 2008;7(6):1569–78.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Chen Q, Manning CD, Millar H, McCabe FL, Ferrante C, Sharp C, et al. CNTO 95, a fully human anti alphav integrin antibody, inhibits cell signaling, migration, invasion, and spontaneous metastasis of human breast cancer cells. Clin Exp Metastasis. 2008;25(2):139–48.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Steglich A, Vehlow A, Eke I, Cordes N. α integrin targeting for radiosensitization of three-dimensionally grown human head and neck squamous cell carcinoma cells. Cancer Lett. 2015;357(2):542–8.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Hehlgans S, Eke I, Cordes N. Targeting FAK radiosensitizes 3-dimensional grown human HNSCC cells through reduced Akt1 and MEK1/2 signaling. Int J Radiat Oncol Biol Phys. 2012;83(5):e669–76.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Hehlgans S, Lange I, Eke I, Cordes N. 3D cell cultures of human head and neck squamous cell carcinoma cells are radiosensitized by the focal adhesion kinase inhibitor TAE226. Radiother Oncol. 2009;92(3):371–8.Google Scholar
  128. 128.
    Tang K-J, Constanzo JD, Venkateswaran N, Melegari M, Ilcheva M, Morales JC, et al. Focal adhesion kinase regulates the DNA damage response and its inhibition Radiosensitizes mutant KRAS lung Cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(23):5851–63.CrossRefGoogle Scholar
  129. 129.
    Graham K, Moran-Jones K, Sansom OJ, Brunton VG, Frame MC. FAK deletion promotes p53-mediated induction of p21, DNA-damage responses and radio-resistance in advanced squamous cancer cells. PLoS One. 2011;6(12):e27806.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612–9.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Dok R, Glorieux M, Holacka K, Bamps M, Nuyts S. Dual role for p16 in the metastasis process of HPV positive head and neck cancers. Mol Cancer. 2017;16:113.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Fåhraeus R, Lane DP. The p16(INK4a) tumour suppressor protein inhibits alphavbeta3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alphavbeta3 to focal contacts. EMBO J. 1999;18(8):2106–18.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    McCormack SJ, Brazinski SE, Moore JL, Werness BA, Goldstein DJ. Activation of the focal adhesion kinase signal transduction pathway in cervical carcinoma cell lines and human genital epithelial cells immortalized with human papillomavirus type 18. Oncogene. 1997;15(3):265–74.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Byers LA, Diao L, Ng PKS, Heymach C, Fan YH, El-Naggar AK, et al. Proteomic profiling of HPV-positive head and neck cancer to identify new candidates for targeted therapy. J Clin Oncol. 2014;32(15_suppl):6030.Google Scholar
  135. 135.
    Du M, Fan X, Hong E, Chen JJ. Interaction of oncogenic papillomavirus E6 proteins with fibulin-1. Biochem Biophys Res Commun. 2002;296(4):962–9.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Vande Pol SB, Brown MC, Turner CE. Association of Bovine Papillomavirus Type 1 E6 oncoprotein with the focal adhesion protein paxillin through a conserved protein interaction motif. Oncogene. 1998;16(1):43–52.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    DeMasi J, Chao MC, Kumar AS, Howley PM. Bovine papillomavirus E7 Oncoprotein inhibits Anoikis. J Virol. 2007;81(17):9419–25.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Huh K-W, DeMasi J, Ogawa H, Nakatani Y, Howley PM, Münger K. Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600. Proc Natl Acad Sci U S A. 2005;102(32):11492–7.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRefGoogle Scholar
  140. 140.
    Kimple RJ, Smith MA, Blitzer GC, Torres AD, Martin JA, Yang RZ, et al. Enhanced radiation sensitivity in HPV-positive head and neck Cancer. Cancer Res. 2013;73(15):4791–800.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Thoracic, Head and Neck Medical Oncology, Division of Cancer MedicineThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Clinical Radiation Oncology, Division of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations