Generic placeholder image

Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

Focal Adhesion Kinase in Ovarian Cancer: A Potential Therapeutic Target for Platinum and Taxane-Resistant Tumors

Author(s): Arkene Levy*, Khalid Alhazzani, Priya Dondapati, Ali Alaseem, Khadijah Cheema, Keerthi Thallapureddy, Paramjot Kaur, Saad Alobid and Appu Rathinavelu

Volume 19, Issue 3, 2019

Page: [179 - 188] Pages: 10

DOI: 10.2174/1568009618666180706165222

Price: $65


Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase, which is an essential player in regulating cell migration, invasion, adhesion, proliferation, and survival. Its overexpression and activation have been identified in sixty-eight percent of epithelial ovarian cancer patients and this is significantly associated with higher tumor stage, metastasis, and shorter overall survival of these patients. Most recently, a new role has emerged for FAK in promoting resistance to taxane and platinum-based therapy in ovarian and other cancers. The development of resistance is a complex network of molecular processes that make the identification of a targetable biomarker in platinum and taxane-resistant ovarian cancer a major challenge. FAK overexpression upregulates ALDH and XIAP activity in platinum-resistant and increases CD44, YB1, and MDR-1 activity in taxaneresistant tumors. FAK is therefore now emerging as a prognostically significant candidate in this regard, with mounting evidence from recent successes in preclinical and clinical trials using small molecule FAK inhibitors. This review will summarize the significance and function of FAK in ovarian cancer, and its emerging role in chemotherapeutic resistance. We will discuss the current status of FAK inhibitors in ovarian cancers, their therapeutic competencies and limitations, and further propose that the combination of FAK inhibitors with platinum and taxane-based therapies could be an efficacious approach in chemotherapeutic resistant disease.

Keywords: Focal adhesion kinase, ovarian cancer, resistance, taxanes, platinum compounds, FAK inhibitors.

Graphical Abstract
Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT. pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 1992; 89: 5192-6.
Ilić D, Furuta Y, Kanazawa S, et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 1995; 377: 539-44.
Romer LH, McLean N, Turner CE, Burridge K. Tyrosine kinase activity, cytoskeletal organization, and motility in human vascular endothelial cells. Mol Biol Cell 1994; 5: 349-61.
Kim I, Kim HG, Moon SO, et al. Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion. Circ Res 2000; 86: 952-9.
Li W, Lee J, Vikis HG, et al. Activation of FAK and Src are receptor-proximal events required for netrin signaling. Nat Neurosci 2004; 7: 1213-21.
Chacón MR, Navarro AI, Cuesto G, et al. Focal adhesion kinase regulates actin nucleation and neuronal filopodia formation during axonal growth. Development 2012; 139: 3200-10.
Hungerford JE, Compton MT, Matter ML, Hoffstrom BG, Otey CA. Inhibition of pp125FAK in cultured fibroblasts results in apoptosis. J Cell Biol 1996; 135: 1383-90.
Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY. Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 1996; 134: 793-9.
Sood AK, Coffin JE, Schneider GB, et al. Biological significance of focal adhesion kinase in ovarian cancer: role in migration and invasion. Am J Pathol 2004; 165: 1087-95.
Corsi JM, Rouer E, Girault JA, Enslen H. Organization and post-transcriptional processing of focal adhesion kinase gene. BMC Genomics 2006; 7: 198.
Grigera PR, Jeffery ED, Martin KH, Shabanowitz J, Hunt DF, Parsons JT. FAK phosphorylation sites mapped by mass spectrometry. J Cell Sci 2005; 118: 4931-5.
Kadaré G, Gervasi N, Brami-Cherrier K, et al. Conformational dynamics of the focal adhesion targeting domain control specific functions of focal adhesion kinase in cells. J Biol Chem 2015; 290(1): 478-91.
Deramaudt TB, Dujardin D, Noulet F, et al. Altering FAK-paxillin interactions reduces adhesion, migration and invasion processes. PLoS One 2014; 9(3): e92059.
Lawson C, Lim S, Uryu XL, Calderwood DA, Schlaepfer DD. FAK promotes recruitment of talin to nascent adhesions to control cell motility. J Cell Biol 2012; 196(2): 223-32.
Ceccarelli DFJ, Song HK, Poy F, Schaller MD, Eck MJ. Crystal structure of the FERM domain of focal adhesion kinase. J Biol Chem 2006; 281: 252-9.
Dunty JM, Gabarra-Niecko V, King ML, Ceccarelli DFJ, Eck MJ, Schaller MD. FERM domain interaction promotes FAK signaling. Mol Cell Biol 2004; 24: 5353-68.
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: 18656-73.
Cheng N, Li Y, Han Z-G. Argonaute2 promotes tumor metastasis by way of up-regulating focal adhesion kinase expression in hepatocellular carcinoma. Hepatology 2013; 57: 1906-18.
Li S, Huang X, Zhang D, et al. Requirement of PEA3 for transcriptional activation of FAK gene in tumor metastasis. PLoS One 2013; 8: e79336.
Kong X, Li G, Yuan Y, et al. MicroRNA-7 inhibits epithelial-to-mesenchymal transition and metastasis of breast cancer cells via targeting FAK expression. PLoS One 2012; 7: e41523.
Cance WG, Golubovskaya VM. Focal adhesion kinase versus p53: apoptosis or survival? Sci Signal 2008; 1(20): pe22.
You D, Xin J, Volk A, et al. FAK mediates a compensatory survival signal parallel to PI3K-AKT in PTEN-Null T-ALL cells. Cell Reports 2015; 10(12): 2056-69.
Golubovskaya VM, Cance WG. Focal adhesion kinase and p53 signaling in cancer cells. Int Rev Cytol 2007; 263(7): 103-53.
Sulzmaier FJ, Jean C, Schlaepfer DD. FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer 2014; 14(9): 598-610.
Ward KK, Tancioni I, Lawson C, et al. Inhibition of Focal Adhesion Kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression. Clin Exp Metastasis 2013; 30(5): 579-94.
Bonome T, Lee JY, Park DC, et al. Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. Cancer Res 2005; 65(22): 10602-12.
Zhang L, Zou W. Inhibition of integrin β1 decreases the malignancy of ovarian cancer cells and potentiates anticancer therapy via the FAK/STAT1 signaling pathway. Mol Med Rep 2015; 12(6): 7869-76.
Grisaru-Granovsky S, Salah Z, Maoz M, Pruss D, Beller U, Bar-Shavit R. Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Int J Cancer 2005; 113: 372-8.
Aust S, Auer K, Bachmayr-Heyda A, et al. Ambivalent role of pFAK-Y397 in serous ovarian cancer-a study of the OVCAD consortium. Mol Cancer 2014; 13: 67.
Lietha D, Cai X, Ceccarelli DF, Li Y, Schaller MD, Eck MJ. Structural basis for the autoinhibition of focal adhesion kinase. Cell 2007; 129: 1177-87.
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: 954-63.
Qi JH, Claesson-Welsh L. VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase. Exp Cell Res 2001; 263(1): 173-82.
Boeuf FL, Houle F, Huot J. Regulation of vascular endothelial growth factor receptor 2-mediated phosphorylation of focal adhesion kinase by heat shock protein 90 and Src kinase activities. J Biol Chem 2004; 279: 39175-85.
Lim Y, Park H, Jeon J, et al. Focal adhesion kinase is negatively regulated by phosphorylation at tyrosine 407. J Biol Chem 2007; 282(14): 10398-404.
Eliceiri BP, Puente XS, Hood JD, et al. Src-mediated coupling of focal adhesion kinase to integrin αvβ5 in vascular endothelial growth factor signaling J. Cell Biol 2002; 157: 149-60.
Chang JF, Guan JL. Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. J Cell Sci 1996; 109(Pt 7): 1787-94.
Cary LA, Han DC, Polte TR, Hanks SK, Guan JL. Identification of p130Cas as a mediator of focal adhesion kinase-promoted cell migration. J Cell Biol 1998; 140(1): 211-21.
Ren XD, Kiosses WB, Sieg DJ, Otey CA, Schlaepfer DD, Schwartz MA. Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover. J Cell Sci 2000; 113(Pt 20): 3673-8.
Hsia DA, Mitra SK, Hauck CR, et al. Differential regulation of cell motility and invasion by FAK. J Cell Biol 2003; 160(5): 753-67.
Serrels B, Serrels A, Brunton VG, et al. Focal adhesion kinase controls actin assembly via a FERM-mediated interaction with the Arp2/3 complex. Nat Cell Biol 2007; 9(9): 1046-56.
Zhao J, Guan JL. Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev 2009; 28: 35-49.
Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 2009; 28(1-2): 15-33.
Zhai J, Lin H, Nie Z, et al. Direct interaction of focal adhesion kinase with p190RhoGEF. J Biol Chem 2003; 278: 24865-73.
Horiuchi A, Imai T, Wang C, et al. Up-regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. Lab Invest 2003; 83: 861-70.
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.
Liu Y, Loijens JC, Martin KH, Karginov AV, Parsons JT. The association of ASAP1, an ADP ribosylation factor-GTPase activating protein, with focal adhesion kinase contributes to the process of focal adhesion assembly. Mol Biol Cell 2002; 13(6): 2147-56.
Wu X, Suetsugu S, Cooper LA, Takenawa T, Guan JL. Focal adhesion kinase regulation of N-WASP subcellular localization and function. J Biol Chem 2004; 279(10): 9565-76.
Kang Y, Hu W, Ivan C, 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.
Xie B, Zhao J, Kitagawa M, et al. Focal adhesion kinase activates Stat1 in integrin-mediated cell migration and adhesion. J Biol Chem 2001; 276: 19512-23.
Zhang L, Wang D, Jiang W, et al. Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium. Reprod Biol Endocrinol 2010; 8: 74.
Xu B, Lefringhouse J, Liu Z, et al. Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy. Oncogenesis 2017; 6(1): e295.
Sawada K, Mitra AK, Radjabi AR, et al. Loss of E-cadherin promotes ovarian cancer metastasis via α5-integrin, which is a therapeutic target. Cancer Res 2008; 68(7): 2329-39.
Golubovskaya VM, Finch R, Zheng M, Kurenova EV, Cance WG. The 7-amino-acid site in the proline-rich region of the N-terminaldomain of p53 is involved in the interaction with FAK and is critical for p53 functioning. Biochem J 2008; 411: 151-60.
Lee JG, Ahn JH, Jin KT, Ho LJ, Choi JH. Mutant p53 promotes ovarian cancer cell adhesion to mesothelial cells via integrin β4 and Akt signals. Sci Rep 2015; 5: 12642.
Golubovskaya VM. Targeting FAK in human cancer: from finding to first clinical trials. Front Biosci 2014; 19: 687-706.
Carpten JD, Faber AL, Horn C, et al. Tucker- Kellogg, G.; Touchman, J.; Patel, K.; Mousses, S.; Bittner, M.; Schevitz, R.; Lai, M.H.; Blanchard, K.L.; Thomas, J.E. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007; 448(7152): 439-44.
Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2015; 65: 5-29.
Judson PL, He X, Cance WG, Van LL. Overexpression of focal adhesion kinase, a protein tyrosine kinase, in ovarian carcinoma. Cancer 1999; 86(8): 1551-6.
Gabriel B, Mildenberger S, Weisser CW, et al. Focal adhesion kinase interacts with the transcriptional coactivator FHL2 and both are overexpressed in epithelial ovarian cancer. Anticancer Res 2004; 24(2B): 921-7.
Gao M, Liu X, Sun H, Ren H, Wang L, Shen Y. Study on FAK regulation of migration of vascular endothelial cells depending upon focal adhesion proteins. J Biomed Eng 2013; 30(3): 567-71.
Li M, Hong L, Liao M, Guo G. Expression and clinical significance of focal adhesion kinase and adrenomedullin in epithelial ovarian cancer. Oncol Lett 2015; 10: 1003-7.
Halder J, Landen CN, Lutgendorf SK, et al. Focal adhesion kinase silencing augments docetaxel-mediated apoptosis in ovarian cancer cells. Clin Cancer Res 2005; 11(24): 8829-36.
Stone RL, Baggerly KA, Armaiz-Pena GN, et al. Focal adhesion kinase: An alternative focus for anti-angiogenesis therapy in ovarian cancer. Cancer Biol Ther 2014; 15(7): 919-29.
Halder J, Kamat AA, Landen CN, et al. 2006.
Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: A meta-analysis. J Clin Oncol 2002; 20(5): 1248-59.
Jelovac D, Armstrong DK. Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin 2011; 61(3): 183-203.
Vasey PA. Resistance to chemotherapy in advanced ovarian cancer: mechanisms and current strategies. Br J Cancer 2003; 89(Suppl. 3): S23-8.
Holzer AK, Manorek GH, Howell SB. Contribution of the major copper influx transporter CTR1 to the cellular accumulation of cisplatin, carboplatin, and oxaliplatin. Mol Pharmacol 2006; 70(4): 1390-4.
Chien J, Kuang R, Landen C, Shridhar V. Platinum-sensitive recurrence in ovarian cancer: the role of tumor microenvironment. Front Oncol 2013; 3: 251.
Bean LM, Sulzmaier FJ, Tancioni I, et al.
Rodriguez-Torres M, Allan AL. Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors. Clin Exp Metastasis 2016; 33: 97-113.
Reboe, M.; Levy, A.; Dhandyuthapani, S.; Rathinavelu, A. Y15 enhances the cytotoxic profile of cisplatin, paclitaxel and vitamin e in platinum resistant ovarian cancer cells. Faseb J., 2015, 29, 785.1.
Fraser M, Leung B, Jahani-Asl A, Yan X, Thompson WE, Tsang BK. Chemoresistance in human ovarian cancer: the role of apoptotic regulators. Reprod Biol Endocrinol 2003; 1: 66.
Yusuf RZ, Duan L, Penson RT, Seiden MV. Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets 2003; 3: 1-19.
McGrail DJ, Khambhati NN, Qi MX, et al. Alterations in ovarian cancer cell adhesion drive taxol resistance by increasing microtubule dynamics in a FAK-dependent manner. Sci Rep 2015; 5: 9529.
Bourguignon LYW, Peyrollier K, Xia W, Gilad E. Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem 2008; 283(25): 17635-51.
Qin S, Li Y, Cao X, Du J, Huang X. NANOG regulates epithelial–mesenchymal transition and chemoresistance in ovarian cancer. Biosci Rep 2017; 37(1): BSR20160247.
Steffensen KD, Alvero AB, Yang Y, et al. Prevalence of epithelial ovarian cancer stem cells correlates with recurrence in early-stage ovarian cancer. J Oncol 2011; 2011: 620523.
Mitra, A.K. In: Ovarian Cancer Metastasis: A Unique Mechanism of Dissemination; Ke Xu, Ed; InTech, 2016; pp. 44-58
Mitamura T, Watari H, Wang L, et al. Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET. Oncogenesis 2013; 2(3): e40.
Kavanagh JJ. Docetaxel in the treatment of ovarian cancer. Oncology 2002; 16(6)(Suppl. 6): 73-81.
Levy AS, Khan Z, Batko S, et al. Proceedings of the AACR 107th Annual Meeting. New Orleans, LA. 2016.
Lu H, Wang L, Gao W, et al. IGFBP2/FAK pathway is causally associated with dasatinib resistance in non-small cell lung cancer cells. Mol Cancer Ther 2013; 12: 2864-73.
Shi Q, Hjelmeland AB, Keir ST, et al. A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth. Mol Carcinog 2007; 46(6): 488-96.
Slack-Davis JK, Martin KH, Tilghman RW, et al. Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem 2007; 282: 14845-52.
Yoon H, Choi Y-L, Song J-Y, et al. Targeted inhibition of FAK, PYK2 and BCL-XL Synergistically enhances apoptosis in ovarian clear cell carcinoma cell lines. PLoS One 2014; 9(2): e88587.
Cance WG, Kurenova E, Marlowe T, Golubovskaya V. Disrupting the scaffold to improve focal adhesion kinase-targeted cancer therapeutics. Sci Signal 2013; 6(268): pe10.
Golubovskaya VM, Ho B, Zheng M, 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.
Golubovskaya VM, Figel S, Ho BT, et al. A small molecule focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2-hydroxyethyl)-3, 5, 7-triaza-1-azoniatricyclo [,7]decane; bromide effectively inhibits FAK autophosphorylation activity and decreases cancer cell viability, clonogenicity and tumor growth in vivo. Carcinogenesis 2012; 33: 1004-13.
Golubovskaya VM, Nyberg C, Zheng M, et al. A small molecule inhibitor, 1,2,4,5-benzenetetraamine tetrahydrochloride, targeting the Y397 site of focal adhesion kinase decreases tumor growth. J Med Chem 2008; 51(23): 7405-16.
Kim J-H, Skates SJ, Uede T, et al. Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA 2002; 287(13): 1671-9.
Tancioni I, Uryu S, Sulzmaier FJ, et al. FAK inhibition disrupts a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth. Mol Cancer Ther 2014; 13(8): 2050-61.
Halder J, Lin YG, Merritt WM, et al. Han. L.Z.; Kim. T.J.; Lu. C.; Tari. A.M.; Bornmann. W.; Fernandez. A.; Lopez-Berestein. G.; Sood, A.K. Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. Cancer Res 2007; 67(22): 10976-83.
Bottsford-Miller J, Sanguino A, Thanapprapasr D, et al. Proceedings of the AACR 102nd Annual Meeting. Orlando, FL. 2011.
Jones SF, Siu LL, Bendell JC, 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 2015; 33(5): 1100-7.
Patel MR, Infante JR, Moore KN, 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 2014; 32(15): 5521-1.
Soria J-C, Gan HK, Arkenau H-T, Blagden SP, Plummer R, Ranson M. Evans. T.R.J.; Zalcman. G.; Bahleda. A.; Hollebecque. A.; Lemech. C.; Dean. E.; Brown. J.; Gibson. D.; Peddareddigari. V.; Murray. S.; Nebot. N.; Mazumdar. J.; Swartz. L.; Auger. K.R.; Fleming. R.A.; Singh. R.; Millward, M. A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors. Ann Oncol 2016; 27(12): 2268-74.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy