Interrupting the FGF19-FGFR4 Axis to Therapeutically Disrupt Cancer Progression

Author(s): Liwei Lang, Austin Y. Shull, Yong Teng*.

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 1 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Coordination between the amplification of the fibroblast growth factor FGF19, overexpression of its corresponding receptor FGFR4, and hyperactivation of the downstream transmembrane enzyme β-klotho has been found to play pivotal roles in mediating tumor development and progression. Aberrant FGF19-FGFR4 signaling has been implicated in driving specific tumorigenic events including cancer cell proliferation, apoptosis resistance, and metastasis by activating a myriad of downstream signaling cascades. As an attractive target, several strategies implemented to disrupt the FGF19-FGFR4 axis have been developed in recent years, and FGF19-FGFR4 binding inhibitors are being intensely evaluated for their clinical use in treating FGF19-FGFR4 implicated cancers. Based on the established work, this review aims to detail how the FGF19-FGFR4 signaling pathway plays a vital role in cancer progression and why disrupting communication between FGF19 and FGFR4 serves as a promising therapeutic strategy for disrupting cancer progression.

Keywords: FGF19, FGFR4, β-klotho, cancer, target, drug development.

Degirolamo, C.; Sabbà, C.; Moschetta, A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat. Rev. Drug Discov., 2016, 15(1), 51-69.
Nishimura, T. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim. Biophys. Acta, 1999, 1444(1), 148-151.
Itoh, N.; Ornitz, D.M. Functional evolutionary history of the mouse Fgf gene family. Dev. Dyn., 2008, 237(1), 18-27.
Mohammadi, M.; Olsen, S.K.; Ibrahimi, O.A. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev., 2005, 16(2), 107-137.
Beenken, A.; Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nat. Rev. Drug Discov., 2009, 8(3), 235-253.
Miura, S.; Mitsuhashi, N.; Shimizu, H.; Kimura, F.; Yoshidome, H.; Otsuka, M.; Kato, A.; Shida, T.; Okamura, D.; Miyazaki, M. Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer, 2012, 12(1), 56.
Desnoyers, L.R.; Pai, R.; Ferrando, R.E.; Hötzel, K.; Le, T.; Ross, J.; Carano, R.; D’souza, A.; Qing, J.; Mohtashemi, I.; Ashkenazi, A. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene, 2008, 27(1), 85-97.
Spinola, M.; Leoni, V.; Pignatiello, C.; Conti, B.; Ravagnani, F.; Pastorino, U.; Dragani, T.A. Functional FGFR4 Gly388Arg polymorphism predicts prognosis in lung adenocarcinoma patients. J. Clin. Oncol., 2005, 23(29), 7307-7311.
Feng, S.; Dakhova, O.; Creighton, C.J.; Ittmann, M. Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression. Cancer Res., 2013, 73(8), 2551-2562.
Buhmeida, A.; Dallol, A.; Merdad, A.; Al-Maghrabi, J.; Gari, M.A.; Abu-Elmagd, M.M.; Chaudhary, A.G.; Abuzenadah, A.M.; Nedjadi, T.; Ermiah, E.; Al-Thubaity, F. High fibroblast growth factor 19 (FGF19) expression predicts worse prognosis in invasive ductal carcinoma of breast. Tumour Biol., 2014, 35(3), 2817-2824.
Tiong, K.H.; Tan, B.S.; Choo, H.L.; Chung, F.F.L.; Hii, L.W.; Tan, S.H.; Khor, N.T.W.; Wong, S.F.; See, S.J.; Tan, Y.F.; Rosli, R. Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival. Oncotarget, 2016, 7(36), 57633.
Zhang, X.; Wang, Z.; Tian, L.; Xie, J.; Zou, G.; Jiang, F. increased expression of fgf19 contributes to tumor progression and cell motility of human thyroid cancer. Otolaryngol. Head Neck Surg., 2016, 154(1), 52-58.
Sawey, E.T.; Chanrion, M.; Cai, C.; Wu, G.; Zhang, J.; Zender, L.; Zhao, A.; Busuttil, R.W.; Yee, H.; Stein, L.; French, D.M. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell, 2011, 19(3), 347-358.
Zhao, H.; Lv, F.; Liang, G.; Huang, X.; Wu, G.; Zhang, W.; Yu, L.; Shi, L.; Teng, Y. FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3beta/beta- catenin signaling cascade via FGFR4 activation. Oncotarget, 2016, 7(12), 13575-13586.
Nicholes, K.; Guillet, S.; Tomlinson, E.; Hillan, K.; Wright, B.; Frantz, G.D.; Pham, T.A.; Dillard-Telm, L.; Tsai, S.P.; Stephan, J.P.; Stinson, J. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am. J. Pathol., 2002, 160(6), 2295-2307.
Uriarte, I.; Latasa, M.U.; Carotti, S.; Fernandez‐Barrena, M.G.; Garcia‐Irigoyen, O.; Elizalde, M.; Urtasun, R.; Vespasiani‐Gentilucci, U.; Morini, S.; de Mingo, A.; Mari, M. Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int. J. Cancer, 2015, 136(10), 2469-2475.
Wang, S.; Zhao, D.; Tian, R.; Shi, H.; Chen, X.; Liu, W.; Wei, L. FGF19 Contributes to Tumor Progression in Gastric Cancer by Promoting Migration and Invasion. Oncol. Res. Featuring Preclin. Clin. Cancer Ther, 2016, 23(4), 197-203.
Hu, L.; Cong, L. Fibroblast growth factor 19 is correlated with an unfavorable prognosis and promotes progression by activating fibroblast growth factor receptor 4 in advanced-stage serous ovarian cancer. Oncol. Rep., 2015, 34(5), 2683-2691.
Cui, Y.; Liu, J.; Liu, Y.; Liu, J.H. Upregulation of FGF19 in lung adenocarcinoma and predicts poor prognosis. Int. J. Clin. Exp. Pathol., 2016, 9(7), 7338-7344.
Valastyan, S.; Weinberg, R.A. Tumor metastasis: molecular insights and evolving paradigms. Cell, 2011, 147(2), 275-292.
Tan, Q.; Li, F.; Wang, G.; Xia, W.; Li, Z.; Niu, X.; Ji, W.; Yuan, H.; Xu, Q.; Luo, Q.; Zhang, J. Identification of FGF19 as a prognostic marker and potential driver gene of lung squamous cell carcinomas in Chinese smoking patients. Oncotarget, 2016, 7(14), 18394.
Teishima, J.; Yano, S.; Shoji, K.; Hayashi, T.; Goto, K.; Kitano, H.; Oka, K.; Nagamatsu, H.; Matsubara, A. Accumulation of FGF9 in prostate cancer correlates with epithelial-to-mesenchymal transition and induction of VEGF-A expression. Anticancer Res., 2014, 34(2), 695-700.
Dienstmann, R.; Rodon, J.; Prat, A.; Perez-Garcia, J.; Adamo, B.; Felip, E.; Cortes, J.; Iafrate, A.J.; Nuciforo, P.; Tabernero, J. Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann. Oncol., 2014, 25(3), 552-563.
Li, S.Q.; Cheuk, A.T.; Shern, J.F.; Song, Y.K.; Hurd, L.; Liao, H.; Wei, J.S.; Khan, J. Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534). PLoS One, 2013, 8(10), e76551.
Gao, L.; Wang, X.; Tang, Y.; Huang, S.; Hu, C.A.A.; Teng, Y. FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J. Exp. Clin. Cancer Res., 2017, 36(1), 8.
Shimizu, M.; Li, J.; Maruyama, R.; Inoue, J.; Sato, R. FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to endoplasmic reticulum stress. Biochem. J., 2013, 450(1), 221-229.
Kurosu, H.; Choi, M.; Ogawa, Y.; Dickson, A.S.; Goetz, R.; Eliseenkova, A.V.; Mohammadi, M.; Rosenblatt, K.P.; Kliewer, S.A.; Kuro-o, M. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem., 2007, 282(37), 26687-26695.
Chiang, J.Y. Bile acids: regulation of synthesis. J. Lipid Res., 2009, 50(10), 1955-1966.
Owen, B.M.; Mangelsdorf, D.J.; Kliewer, S.A. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol. Metab., 2015, 26(1), 22-29.
Wu, X.; Ge, H.; Gupte, J.; Weiszmann, J.; Shimamoto, G.; Stevens, J.; Hawkins, N.; Lemon, B.; Shen, W.; Xu, J.; Veniant, M.M. Co-receptor requirements for fibroblast growth factor-19 signaling. J. Biol. Chem., 2007, 282(40), 29069-29072.
Poh, W.; Wong, W.; Ong, H.; Aung, M.O.; Lim, S.G.; Chua, B.T.; Ho, H.K. Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma. Mol. Cancer, 2012, 11(1), 14.
Feng, S.; Dakhova, O.; Creighton, C.J.; Ittmann, M. Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression. Cancer Res., 2013, 73(8), 2551-2562.
Xu, Y.F.; Yang, X.Q.; Lu, X.F.; Guo, S.; Liu, Y.; Iqbal, M.; Ning, S.L.; Yang, H.; Suo, N.; Chen, Y.X. Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma. Biochem. Biophys. Res. Commun., 2014, 446(1), 54-60.
Peláez-García, A.; Barderas, R.; Torres, S.; Hernández-Varas, P.; Teixidó, J.; Bonilla, F.; de Herreros, A.G.; Casal, J.I. FGFR4 role in epithelial-mesenchymal transition and its therapeutic value in colorectal cancer. PLoS One, 2013, 8(5), e63695.
Zhao, Y.; Meng, C.; Wang, Y.; Huang, H.; Liu, W.; Zhang, J.F.; Zhao, H.; Feng, B.; Leung, P.S.; Xia, Y. IL-1β inhibits β-Klotho expression and FGF19 signaling in hepatocytes. Am. J. Physiol. Endocrinol. Metab., 2016, 310(4), E289-E300.
Makishima, M.; Okamoto, A.Y.; Repa, J.J.; Tu, H.; Learned, R.M.; Luk, A.; Hull, M.V.; Lustig, K.D. Identification of a nuclear receptor for bile acids. Science, 1999, 284(5418), 1362-1365.
Miyata, M.; Hata, T.; Yamakawa, H.; Kagawa, T.; Yoshinari, K.; Yamazoe, Y. Involvement of multiple elements in FXR-mediated transcriptional activation of FGF19. J. Steroid Biochem. Mol. Biol., 2012, 132(1), 41-47.
Wang, H.; Venkatesh, M.; Li, H.; Goetz, R.; Mukherjee, S.; Biswas, A.; Zhu, L.; Kaubisch, A.; Wang, L.; Pullman, J.; Whitney, K. Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice. J. Clin. Invest., 2011, 121(8), 3220-3232.
Schmidt, D.R.; Holmstrom, S.R.; Tacer, K.F.; Bookout, A.L.; Kliewer, S.A.; Mangelsdorf, D.J. Regulation of bile acid synthesis by fat-soluble vitamins A and D. J. Biol. Chem., 2010, 285(19), 14486-14494.
Wistuba, W.; Gnewuch, C.; Liebisch, G.; Schmitz, G.; Langmann, T. Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR. World J. Gastroenterol., 2007, 13(31), 4230.
Cheng, J.; Fang, Z.Z.; Nagaoka, K.; Okamoto, M.; Qu, A.; Tanaka, N.; Kimura, S.; Gonzalez, F.J. Activation of Intestinal Human Pregnane X Receptor Protects against Azoxymethane/Dextran Sulfate Sodium–Induced Colon Cancer. J. Pharmacol. Exp. Ther., 2014, 351(3), 559-567.
Pai, R.; French, D.; Ma, N.; Hotzel, K.; Plise, E.; Salphati, L.; Setchell, K.D.; Ware, J.; Lauriault, V.; Schutt, L.; Hartley, D. Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys. Toxicol. Sci., 2012, 126(2), 446-456.
Ornitz, D.M.; Itoh, N. The fibroblast growth factor signaling pathway. Dev. Biol., 2015, 4(3), 215-266.
Fon Tacer, K.; Bookout, A.L.; Ding, X.; Kurosu, H.; John, G.B.; Wang, L.; Goetz, R.; Mohammadi, M.; Kuro-o, M.; Mangelsdorf, D.J.; Kliewer, S.A. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol. Endocrinol., 2010, 24(10), 2050-2064.
Mencke, R.; Olauson, H.; Hillebrands, J-L. Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies. Adv. Drug Deliv. Rev., 2017, 121, 85-100.
Hu, M.C.; Shi, M.; Cho, H.J.; Adams-Huet, B.; Paek, J.; Hill, K.; Shelton, J.; Amaral, A.P.; Faul, C.; Taniguchi, M.; Wolf, M. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J. Am. Soc. Nephrol., 2015, 26(6), 1290-1302.
Chen, T.H.; Kuro-o, M.; Chen, C.H.; Sue, Y.M.; Chen, Y.C.; Wu, H.H.; Cheng, C.Y. The secreted Klotho protein restores hosphate retention and suppresses accelerated aging in Klotho mutant mice. Eur. J. Pharmacol., 2013, 698(1), 67-73.
Goetz, R. Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. Mol. Cell. Biol., 2012, 32(10), 1944-1954.
Turner, N.; Grose, R. Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer, 2010, 10(2), 116-129.
Heinzle, C.; Erdem, Z.; Paur, J.; Grasl-Kraupp, B.; Holzmann, K.; Grusch, M.; Berger, W.; Marian, B. Is fibroblast growth factor receptor 4 a suitable target of cancer therapy? Curr. Pharm. Des., 2014, 20(17), 2881-2898.
Cavallaro, U.; Niedermeyer, J.; Fuxa, M.; Christofori, G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat. Cell Biol., 2001, 3(7), 650.
Turkington, R.C.; Longley, D.B.; Allen, W.L.; Stevenson, L.; McLaughlin, K.; Dunne, P.D.; Blayney, J.K.; Salto-Tellez, M.; Van Schaeybroeck, S.; Johnston, P.G. Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer. Cell Death Dis., 2014, 5(2), e1046.
Zaid, T.M.; Yeung, T.L.; Thompson, M.S.; Leung, C.S.; Harding, T.; Schmandt, R.S.; Kwan, S.Y.; Rodriguez-Aguay, C.; Lopez-Berestein, G.; Sood, A.K.; Wong, K.K. Identification of FGFR4 as a potential therapeutic target for advanced-stage, high-grade serous ovarian cancer. Clin. Cancer Res., 2013, 19(4), 809-820.
Shi, S.; Li, X.; You, B.; Shan, Y.; Cao, X.; You, Y. High expression of FGFR4 enhances tumor growth and metastasis in nasopharyngeal carcinoma. J. Cancer, 2015, 6(12), 1245.
Shah, R.N.; Ibbitt, J.C.; Alitalo, K.; Hurst, H.C. FGFR4 overexpression in pancreatic cancer is mediated by an intronic enhancer activated by HNF1α. Oncogene, 2002, 21(54), 8251.
French, D.M.; Lin, B.C.; Wang, M.; Adams, C.; Shek, T.; Hötzel, K.; Bolon, B.; Ferrando, R.; Blackmore, C.; Schroeder, K.; Rodriguez, L.A. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One, 2012, 7(5), e36713.
Wolf, J.; LoRusso, P.M.; Camidge, R.D.; Perez, J.M.; Tabernero, J.; Hidalgo, M.; Schuler, M.; Tian, G.G.; Soria, J.C.; Delord, J.P.; Campone, M. Abstract LB-122: A phase I dose escalation study of NVP-BGJ398, a selective pan FGFR inhibitor in genetically preselected advanced solid tumors. Cancer Res., 2012, 72(8)(Suppl.), LB-122-LB-122.
Gavine, P.R.; Mooney, L.; Kilgour, E.; Thomas, A.P.; Al-Kadhimi, K.; Beck, S.; Rooney, C.; Coleman, T.; Baker, D.; Mellor, M.J.; Brooks, A.N. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res., 2012, 72(8), 2045-2056.
Tan, L.; Wang, J.; Tanizaki, J.; Huang, Z.; Aref, A.R.; Rusan, M.; Zhu, S.J.; Zhang, Y.; Ercan, D.; Liao, R.G.; Capelletti, M. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. Proc. Natl. Acad. Sci., 2014, 111(45), E4869-E4877.
Tabernero, J.; Bahleda, R.; Dienstmann, R.; Infante, J.R.; Mita, A.; Italiano, A.; Calvo, E.; Moreno, V.; Adamo, B.; Gazzah, A.; Zhong, B.; Phase, I. Dose-Escalation Study of JNJ-42756493, an Oral Pan–Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J. Clin. Oncol., 2015, 33(30), 3401-3408.
Tie, J.; Bang, Y.J.; Park, Y.S.; Kang, Y.K.; Monteith, D.; Hartsock, K.; Thornton, D.E.; Michael, M. Abstract CT215: A phase I trial of LY2874455, a fibroblast growth factor receptor inhibitor, in patients with advanced cancer. Cancer Res., 2014, 74(19)(Suppl.), CT215-CT215.
Repana, D.; Ross, P. Targeting FGF19/FGFR4 Pathway: A Novel Therapeutic Strategy for Hepatocellular Carcinoma. Diseases, 2015, 3(4), 294-305.
Hagel, M.; Miduturu, C.; Sheets, M.; Rubin, N.; Weng, W.; Stransky, N.; Bifulco, N.; Kim, J.L.; Hodous, B.; Brooijmans, N.; Shutes, A. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov., 2015, 5(4), 424-437.
Bartz, R.; Fukuchi, K.; Lange, T.; Gruner, K.; Ohtsuka, T.; Watanabe, I.; Hayashi, S.; Redondo-Müller, M.; Takahashi, M.; Agatsuma, T.; Bange, J. U3-1784, a human anti-FGFR4 antibody for the treatment of cancer. Cancer Res., 2016, 76(14)(Suppl.), 3852-3852.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [17 - 25]
Pages: 9
DOI: 10.2174/1568009618666180319091731
Price: $58

Article Metrics

PDF: 34