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:

Targeting FAK in anticancer combination therapies

Nature Reviews Cancer volume 21, pages 313–324 (2021)Cite this article

Subjects

Abstract

Focal adhesion kinase (FAK) is both a non-receptor tyrosine kinase and an adaptor protein that primarily regulates adhesion signalling and cell migration, but FAK can also promote cell survival in response to stress. FAK is commonly overexpressed in cancer and is considered a high-value druggable target, with multiple FAK inhibitors currently in development. Evidence suggests that in the clinical setting, FAK targeting will be most effective in combination with other agents so as to reverse failure of chemotherapies or targeted therapies and enhance efficacy of immune-based treatments of solid tumours. Here, we discuss the recent preclinical evidence that implicates FAK in anticancer therapeutic resistance, leading to the view that FAK inhibitors will have their greatest utility as combination therapies in selected patient populations.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: FAK mediates resistance to therapy in high-grade serous ovarian cancer.
Fig. 2: Molecular targets for FAK inhibitor combination therapy.
Fig. 3: FAK regulates adaptive resistance to targeted therapy in melanoma.
Fig. 4: FAK mediates protective effects of the tumour immune microenvironment, creating opportunities for combination therapy.

Similar content being viewed by others

References

  1. Lee, B. Y., Timpson, P., Horvath, L. G. & Daly, R. J. FAK signaling in human cancer as a target for therapeutics. Pharmacol. Ther. 146, 132–149 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Sulzmaier, F. J., Jean, C. & Schlaepfer, D. D. FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer 14, 598–610 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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 

  4. Acebron, I. et al. Structural basis of focal adhesion kinase activation on lipid membranes. EMBO J. 39, e104743 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Sanchez-Vega, F. et al. Oncogenic signaling pathways in the Cancer Genome Atlas. Cell 173, 321–337.e10 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kaveh, F. et al. A systematic comparison of copy number alterations in four types of female cancer. BMC Cancer 16, 913 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Feng, X. et al. A platform of synthetic lethal gene interaction networks reveals that the GNAQ uveal melanoma oncogene controls the hippo pathway through FAK. Cancer Cell 35, 457–472 (2019). This study establishes FAK as a therapeutic target for the treatment of uveal melanoma with oncogenic mutations in GNAQ heterotrimeric G proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kim, Y. H. et al. FAK-copy-gain is a predictive marker for sensitivity to FAK inhibition in breast cancer. Cancers 11, 1288 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  10. Agochiya, M. et al. Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells. Oncogene 18, 5646–5653 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Gorringe, K. L. et al. Copy number analysis identifies novel interactions between genomic loci in ovarian cancer. PLoS ONE 5, e11408 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Ramakrishna, M. et al. Identification of candidate growth promoting genes in ovarian cancer through integrated copy number and expression analysis. PLoS ONE 5, e9983 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang, H. et al. Gain-of-function RHOA mutations promote focal adhesion kinase activation and dependency in diffuse gastric cancer. Cancer Discov. 10, 288–305 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Serrels, A. et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160–173 (2015). This study is the first to show that nuclear FAK promotes a suppressive immune environment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Naser, R., Aldehaiman, A., Diaz-Galicia, E. & Arold, S. T. Endogenous control mechanisms of FAK and PYK2 and their relevance to cancer development. Cancers 10, 196 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  18. Gao, C. et al. FAK/PYK2 promotes the Wnt/β-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3β. eLife 4, e10072 (2015).

    Article  PubMed Central  Google Scholar 

  19. 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 

  20. Thul, P. J. et al. A subcellular map of the human proteome. Science 356, eaal3321 (2017).

    Article  PubMed  CAS  Google Scholar 

  21. Zhao, J., Zheng, C. & Guan, J. Pyk2 and FAK differentially regulate progression of the cell cycle. J. Cell Sci. 113, 3063–3072 (2000).

    Article  CAS  PubMed  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. 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 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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 

  26. Hirt, U. A. et al. Efficacy of the highly selective focal adhesion kinase inhibitor BI 853520 in adenocarcinoma xenograft models is linked to a mesenchymal tumor phenotype. Oncogenesis 7, 21 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Klaeger, S. et al. The target landscape of clinical kinase drugs. Science 358, eaan4368 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 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 

  29. 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 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. 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 

  34. Soria, J. C. et al. A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors. Ann. Oncol. 27, 2268–2274 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Shimizu, T. et al. A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors. Cancer Chemother. Pharmacol. 77, 997–1003 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jones, S. F. et al. A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors. Invest. New Drugs 33, 1100–1107 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Gerber, D. E. et al. Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer. Lung Cancer 139, 60–67 (2020).

    Article  PubMed  Google Scholar 

  38. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Luke, J. J., Flaherty, K. T., Ribas, A. & Long, G. V. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat. Rev. Clin. Oncol. 14, 463–482 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Diaz Osterman, C. J. et al. FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy. eLife 8, e47327 (2019). This study demonstrates that WNT–β-catenin signalling activated by anchorage-independent activation of FAK supports platinum chemoresistance in ovarian cancer.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016). This study demonstrates that FAK inhibition in PDAC tumours can overcome an immunosuppressive fibrotic tumour microenvironment and render tumours responsive to immunotherapy and chemotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Skinner, H. D. et al. Proteomic profiling identifies PTK2/FAK as a driver of radioresistance in HPV-negative head and neck cancer. Clin. Cancer Res. 22, 4643–4650 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tang, K.-J. et al. Focal adhesion kinase regulates the DNA damage response and its inhibition radiosensitizes mutant KRAS lung cancer. Clin. Cancer Res. 22, 5851–5863 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Williams, K. E., Bundred, N. J., Landberg, G., Clarke, R. B. & Farnie, G. Focal adhesion kinase and Wnt signaling regulate human ductal carcinoma in situ stem cell activity and response to radiotherapy. Stem Cell 33, 327–341 (2015).

    Article  CAS  Google Scholar 

  46. Chen, G. et al. Wnt/beta-catenin pathway activation mediates adaptive resistance to BRAF inhibition in colorectal cancer. Mol. Cancer Ther. 17, 806–813 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. Fallahi-Sichani, M. et al. Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Mol. Syst. Biol. 13, 905 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Hirata, E. et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell 27, 574–588 (2015). This study uses intravital imaging to identify how molecularly targeted therapy can activate the tumour stroma to rapidly promote a drug-tolerant environment and protect melanoma cells via activation of FAK from cell death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Canel, M. et al. T-cell co-stimulation in combination with targeting FAK drives enhanced anti-tumor immunity. eLife 9, e48092 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Serrels, B. et al. IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks. Sci. Signal. 10, eaan8355 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Dawson, J. C. et al. A synergistic anticancer FAK and HDAC inhibitor combination discovered by a novel chemical-genetic high-content phenotypic screen. Mol. Cancer Ther. 19, 637–649 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Tavora, B. et al. Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy. Nature 514, 112–116 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wu, H. J., Hao, M., Yeo, S. K. & Guan, J. L. FAK signaling in cancer-associated fibroblasts promotes breast cancer cell migration and metastasis by exosomal miRNAs-mediated intercellular communication. Oncogene 39, 2539–2549 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zaghdoudi, S. et al. FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer. EMBO Mol. Med. 12, e12010 (2020). This study identifies stromal activation of FAK as an independent prognostic marker for disease-free survival in pancreatic cancer and highlights the potential of targeting the tumour stroma for the treatment of cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tang, J. et al. Drug target commons: a community effort to build a consensus knowledge base for drug-target interactions. Cell Chem. Biol. 25, 224–229 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Patel, M. R. et al. Phase 1/1b study of the FAK inhibitor defactinib (VS-6063) in combination with weekly paclitaxel for advanced ovarian cancer. J. Clin. Oncol. 32, 5521–5521 (2014).

    Article  Google Scholar 

  57. Aung, K. L. et al. A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma (PDAC) (MOBILITY-002 Trial, NCT02428270). J. Clin. Oncol. 36, 409–409 (2018).

    Article  Google Scholar 

  58. Mak, G. et al. A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours. Br. J. Cancer 120, 975–981 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04625270 (2020).

  60. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04620330 (2020).

  61. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04331041 (2020).

  62. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04109456 (2020).

  63. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04201145 (2020).

  64. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03875820 (2020).

  65. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03727880 (2020).

  66. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03287271 (2020).

  67. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02758587 (2018).

  68. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02546531 (2020).

  69. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  71. Ducie, J. et al. Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma. Nat. Commun. 8, 990 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Matulonis, U. A. et al. Ovarian cancer. Nat. Rev. Dis. Primers 2, 16061 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Lee, J. M., Minasian, L. & Kohn, E. C. New strategies in ovarian cancer treatment. Cancer 125 (Suppl. 24), 4623–4629 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. Laklai, H. et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22, 497–505 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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 

  76. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01778803 (2017).

  77. Walton, J. et al. CRISPR/Cas9-Mediated Trp53 and Brca2 knockout to generate improved murine models of ovarian high-grade serous carcinoma. Cancer Res. 76, 6118–6129 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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 

  79. Nagaraj, A. B. et al. Critical role of Wnt/beta-catenin signaling in driving epithelial ovarian cancer platinum resistance. Oncotarget 6, 23720–23734 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Kolev, V. N. et al. Inhibition of FAK kinase activity preferentially targets cancer stem cells. Oncotarget 8, 51733–51747 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Kazi, J. U., Kabir, N. N. & Ronnstrand, L. Brain-expressed X-linked (BEX) proteins in human cancers. Biochim. Biophys. Acta 1856, 226–233 (2015).

    CAS  PubMed  Google Scholar 

  82. Delaney, J. R. et al. Haploinsufficiency networks identify targetable patterns of allelic deficiency in low mutation ovarian cancer. Nat. Commun. 8, 14423 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lengyel, E., Makowski, L., DiGiovanni, J. & Kolonin, M. G. Cancer as a matter of fat: the crosstalk between adipose tissue and tumors. Trends Cancer 4, 374–384 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jana, S. et al. SOX9: The master regulator of cell fate in breast cancer. Biochem. Pharmacol. 174, 113789 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kang, Y. et al. Adrenergic stimulation of DUSP1 impairs chemotherapy response in ovarian cancer. Clin. Cancer Res. 22, 1713–1724 (2016).

    Article  CAS  PubMed  Google Scholar 

  86. Ma, Q. et al. Super-enhancer redistribution as a mechanism of broad gene dysregulation in repeatedly drug-treated cancer cells. Cell Rep. 31, 107532 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. Hobbs, G. A., Der, C. J. & Rossman, K. L. RAS isoforms and mutations in cancer at a glance. J. Cell Sci. 129, 1287–1292 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kim, M. H. et al. Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 35, 462–478 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Shinde, R. et al. Abstract CT143: phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers. Cancer Res. 80, CT143 (2020).

    Google Scholar 

  90. Verastem Oncology. Addressing RAS pathway blockade and resistance. Verastem https://investor.verastem.com/static-files/93835009-c4b6-4818-9075-16cb64237930 (2020).

  91. Zheng, Y. et al. FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. Mol. Cell 35, 11–25 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Horton, E. R. et al. Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly. Nat. Cell Biol. 17, 1577–1587 (2015). This study defines a core machinery that is required for integrin-based focal adhesions in cells attached to fibronectin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kim, N. G. & Gumbiner, B. M. Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. J. Cell Biol. 210, 503–515 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP and TAZ: a signalling hub of the tumour microenvironment. Nat. Rev. Cancer 19, 454–464 (2019).

    Article  CAS  PubMed  Google Scholar 

  95. Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP/TAZ at the roots of cancer. Cancer Cell 29, 783–803 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zanconato, F., Battilana, G., Cordenonsi, M. & Piccolo, S. YAP/TAZ as therapeutic targets in cancer. Curr. Opin. Pharmacol. 29, 26–33 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lin, L. et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet. 47, 250–256 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Li, H. et al. YAP/TAZ activation drives uveal melanoma initiation and progression. Cell Rep. 29, 3200–3211 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Paradis, J. S. et al. Synthetic lethal screens reveal co-targeting FAK and MEK as a multimodal precision therapy for GNAQ-driven uveal melanoma. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-20-3363 (2021).

  100. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04720417 (2021).

  101. Elbediwy, A. et al. Integrin signalling regulates YAP and TAZ to control skin homeostasis. Development 143, 1674–1687 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Han, H. et al. Hippo signaling dysfunction induces cancer cell addiction to YAP. Oncogene 37, 6414–6424 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Suraweera, A., O’Byrne, K. J. & Richard, D. J. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi. Front. Oncol. 8, 92 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Liu-Chittenden, Y. et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26, 1300–1305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zanconato, F. et al. Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4. Nat. Med. 24, 1599–1610 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Linsley, P. S. et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 174, 561–569 (1991).

    Article  CAS  PubMed  Google Scholar 

  108. Linsley, P. S., Clark, E. A. & Ledbetter, J. A. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc. Natl Acad. Sci. USA 87, 5031–5035 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Whitney, G. S. et al. Human T and B lymphocytes express a structurally conserved focal adhesion kinase, pp125FAK. DNA Cell Biol. 12, 823–830 (1993).

    Article  CAS  PubMed  Google Scholar 

  110. Chapman, N. M., Connolly, S. F., Reinl, E. L. & Houtman, J. C. Focal adhesion kinase negatively regulates Lck function downstream of the T cell antigen receptor. J. Immunol. 191, 6208–6221 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Courtney, A. H. et al. A phosphosite within the SH2 domain of lck regulates its activation by CD45. Mol. Cell 67, 498–511.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chapman, N. M. & Houtman, J. C. Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement. Immunol. Res. 59, 23–34 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Raab, M. et al. LFA-1 activates focal adhesion kinases FAK1/PYK2 to generate LAT-GRB2-SKAP1 complexes that terminate T-cell conjugate formation. Nat. Commun. 8, 16001 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gett, A. V., Sallusto, F., Lanzavecchia, A. & Geginat, J. T cell fitness determined by signal strength. Nat. Immunol. 4, 355–360 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Iezzi, G., Karjalainen, K. & Lanzavecchia, A. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8, 89–95 (1998).

    Article  CAS  PubMed  Google Scholar 

  116. Wiemer, A. J. et al. The focal adhesion kinase inhibitor PF-562,271 impairs primary CD4+ T cell activation. Biochem. Pharmacol. 86, 770–781 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Batista, S. et al. Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis. Nat. Commun. 5, 5054 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Lechertier, T. et al. Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth. Nat. Commun. 11, 2810 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tavora, B. et al. Endothelial FAK is required for tumour angiogenesis. EMBO Mol. Med. 2, 516–528 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Pedrosa, A. R. et al. Tumor angiogenesis is differentially regulated by phosphorylation of endothelial cell focal adhesion kinase tyrosines-397 and -861. Cancer Res. 79, 4371–4386 (2019).

    Article  CAS  PubMed  Google Scholar 

  121. Jean, C. et al. Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function. J. Cell Biol. 204, 247–263 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Demircioglu, F. et al. Cancer associated fibroblast FAK regulates malignant cell metabolism. Nat. Commun. 11, 1290 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhang, J. et al. Focal adhesion kinase-promoted tumor glucose metabolism is associated with a shift of mitochondrial respiration to glycolysis. Oncogene 35, 1926–1942 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Jiang, H. et al. Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion. Gut 69, 122–132 (2020).

    Article  CAS  PubMed  Google Scholar 

  125. Vennin, C. et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci. Transl Med. 9, eaai8504 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. de Jonge, M. J. A. et al. Phase I study of BI 853520, an inhibitor of focal adhesion kinase, in patients with advanced or metastatic nonhematologic malignancies. Target. Oncol. 14, 43–55 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Schoenherr, C. et al. Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks. eLife 6, e23172 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  129. Luo, M. et al. Distinct FAK activities determine progenitor and mammary stem cell characteristics. Cancer Res. 73, 5591–5602 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Gao, H. et al. FAK-targeting PROTAC as a chemical tool for the investigation of non-enzymatic FAK function in mice. Protein Cell 11, 534–539 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Cromm, P. M., Samarasinghe, K. T. G., Hines, J. & Crews, C. M. Addressing kinase-independent functions of Fak via PROTAC-mediated degradation. J. Am. Chem. Soc. 140, 17019–17026 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Popow, J. et al. Highly selective PTK2 proteolysis targeting chimeras to probe focal adhesion kinase scaffolding functions. J. Med. Chem. 62, 2508–2520 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. Bantscheff, M. et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat. Biotechnol. 25, 1035–1044 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Ma, H., Deacon, S. & Horiuchi, K. The challenge of selecting protein kinase assays for lead discovery optimization. Expert Opin. Drug Discov. 3, 607–621 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Frame, M. C. & Serrels, A. FAK to the rescue: activated stroma promotes a “safe haven” for BRAF-mutant melanoma cells by inducing FAK signaling. Cancer Cell 27, 429–431 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Guan, J. L. & Shalloway, D. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 358, 690–692 (1992).

    Article  CAS  PubMed  Google Scholar 

  138. Schaller, M. D. et al. pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc. Natl Acad. Sci. USA 89, 5192–5196 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hanks, S. K., Calalb, M. B., Harper, M. C. & Patel, S. K. Focal adhesion protein-tyrosine kinase phosphorylated in response to cell attachment to fibronectin. Proc. Natl Acad. Sci. USA 89, 8487–8491 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

M.C.F. is supported by a Cancer Research UK Programme Award (C157/A24837). J.C.D. is supported by a Cancer Research UK (C42454/A28596) and BrainTumour Charity (GN-000676) award. D.D.S. and D.G.S. are supported by funding from the US National Institutes of Health (R01 CA247562 and R01 CA254342). A.S. is supported by a Cancer Research UK Career Development Award (C39669/A25919).

Author information

Authors and Affiliations

  1. Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    John C. Dawson & Margaret C. Frame

  2. Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK

    Alan Serrels

  3. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Diego Moores Cancer Centre, La Jolla, CA, USA

    Dwayne G. Stupack & David D. Schlaepfer

Authors
  1. John C. Dawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Serrels
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dwayne G. Stupack
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David D. Schlaepfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Margaret C. Frame
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors made a substantial contribution to discussion of the content and writing the article. M.C.F., J.C.D., A.S., D.G.S. and D.D.S. researched data for the article. M.C.F., J.C.D., D.G.S. and D.D.S. reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to John C. Dawson or Margaret C. Frame.

Ethics declarations

Competing interests

A.S. has received research funding from Boehringer Ingelheim to work on IN10018 (then BI 853520) and is on the scientific advisory board of InxMed in relation to the development of IN10018. All other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Cancer thanks J.-L. Guan, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

COSMIC database: https://cancer.sanger.ac.uk/cosmic

TCGA research network genomic data commons portal: https://portal.gdc.cancer.gov/

Glossary

Focal adhesions

Points of cellular plasma membranes that link to extracellular matrix via transmembrane receptors, typically integrin heterodimers.

Focal adhesion targeting (FAT) domain

A protein domain that is involved in the localization of focal adhesion kinase (FAK) to focal adhesions through interactions with other focal adhesion proteins.

FERM (4.1 protein, ezrin, radixin and moesin) domain

A protein domain that is involved in localizing proteins to the plasma membrane.

Heterotrimeric G proteins

A GTPase complex made up of three subunits, α, β and γ, that links transmembrane receptors to intracellular signalling pathways.

Ras homologue family member A

(RHOA). A small GTPase primarily associated with regulating the actin cytoskeleton.

Programmed cell death 1

(PD1). A protein expressed on the surface of cells that inhibits the activation of the immune system.

Stromal cells

Connective tissue cells such as fibroblasts that support the other cells of that organ.

Hippo pathway

A signalling pathway that controls organ size by regulating cell proliferation and apoptosis that can be dysregulated in cancer.

Consensus integrin adhesome

The proteins that make up the core cell adhesion machinery of integrin adhesion complexes.

Regulatory T cells

(Treg cells). A subpopulation of T cells that suppress the immune response.

Cytotoxic T lymphocyte antigen 4

(CTLA4). A protein expressed by regulatory T cells that functions as an immune check point to inhibit the immune response.

RHO-associated protein kinase

(ROCK). A serine/threonine kinase downstream effector of RAS homologue family member A (RHOA) involved in the formation of actin stress fibres.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dawson, J.C., Serrels, A., Stupack, D.G. et al. Targeting FAK in anticancer combination therapies. Nat Rev Cancer 21, 313–324 (2021). https://doi.org/10.1038/s41568-021-00340-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-021-00340-6

This article is cited by

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