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Structural Alterations in Human Fibroblast Growth Factor Receptors in Carcinogenesis

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Abstract

Fibroblast growth factor (FGF) plays an important role in human embryogenesis, angiogenesis, cell proliferation, and differentiation. Carcinogenesis is accompanied by aberrant constitutive activation of FGF receptors (FGFRs) resulting from missense mutation in the FGFR1-4 genes, generation of chimeric oncogenes, FGFR1-4 gene amplification, alternative splicing shift toward formation of mesenchymal FGFR isoforms, and FGFR overexpression. Altogether, these alterations contribute to auto-and paracrine stimulation of cancer cells and neoangiogenesis. Certain missense mutations are found at a high rate in urinary bladder cancer and can be used for non-invasive cancer recurrence diagnostics by analyzing urine cell pellet DNA. Chimeric FGFR1/3 and amplified FGFR1/2 genes can predict cell response to the targeted therapy in various oncological diseases. In recent years, high-throughput sequencing has been used to analyze exomes of virtually all human tumors, which allowed to construct phylogenetic trees of clonal cancer evolution with special emphasis on driver mutations in FGFR1-4 genes. At present, FGFR blockers, such as multi-kinase inhibitors, specific FGFR inhibitors, and FGF ligand traps are being tested in clinical trials. In this review, we discuss current data on the functioning of the FGFR family proteins in both normal and cancer cells, mutations in the FGFR1-4 genes, and mechanisms underlying their oncogenic potential, which might be interesting to a broad range of scientists searching for specific tumor markers and targeted anti-cancer drugs.

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Abbreviations

FGF:

fibroblast growth factor

FGFR:

FGF receptor

References

  1. Krasil’nikov, M. A., and Zborovskaya, I. B. (2016) Molecular Carcinogenesis [in Russian], ID ABV–press, Moscow.

    Google Scholar 

  2. Helsten, T., Schwaederle, M., and Kurzrock, R. (2015) Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications, Cancer Metastasis Rev., 34, 479–496.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Kushlinskiy, N. E., Mazurenko, N. N., and Nemtsova, M. V. (2016) Molecular and Genetic Tumor Markers [in Russian], RAMN Publisher, Moscow.

    Google Scholar 

  4. Zhang, X., and Zhang, Y. (2015) Bladder cancer and genetic mutations, Cell Biochem. Biophys., 73, 65–69.

    Article  PubMed  CAS  Google Scholar 

  5. Brewer, J. R., Mazot, P., and Soriano, P. (2016) Genetic insights into the mechanisms of Fgf signaling, Genes Dev., 30, 751–771.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Martino, E., Tomlinson, D. C., Williams, S. V., and Knowles, M. A. (2016) A place for precision medicine in bladder cancer: targeting the FGFRs, Future Oncol., 12, 2243–2263.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Touat, M., Ileana, E., Postel–Vinay, S., Andre, F., and Soria, J. C. (2015) Targeting FGFR signaling in cancer, Clin. Cancer Res., 21, 2684–2694.

    Article  PubMed  CAS  Google Scholar 

  8. Salazar, L., Kashiwada, T., Krejci, P., Meyer, A. N., Casale, M., Hallowell, M., Wilcox, W. R., Donoghue, D. J., and Thompson, L. M. (2014) Fibroblast growth factor receptor 3 interacts with and activates TGFbeta–activated kinase 1 tyrosine phosphorylation and NFkappaB signaling in multiple myeloma and bladder cancer, PLoS One, 9, e86470.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. De Luca, A., Frezzetti, D., Gallo, M., and Normanno, N. (2017) FGFR–targeted therapeutics for the treatment of breast cancer, Expert Opin. Investig. Drugs, 26, 303–311.

    Article  PubMed  CAS  Google Scholar 

  10. Masoumi–Moghaddam, S., Amini, A., and Morris, D. L. (2014) The developing story of sprouty and cancer, Cancer Metastasis Rev., 33, 695–720.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Winterhoff, B., and Konecny, G. E. (2017) Targeting fibroblast growth factor pathways in endometrial cancer, Curr. Probl. Cancer, 41, 37–47.

    Article  PubMed  Google Scholar 

  12. Porta, R., Borea, R., Coelho, A., Khan, S., Araujo, A., Reclusa, P., Franchina, T., van der Steen, N., van Dam, P., Ferri, J., Sirera, R., Naing, A., Hong, D., and Rolfo, C. (2017) FGFR a promising druggable target in cancer: molecular biology and new drugs, Crit. Rev. Oncol. Hematol., 113, 256–267.

    Article  PubMed  Google Scholar 

  13. Zhou, W. Y., Zheng, H., Du, X. L., and Yang, J. L. (2016) Characterization of FGFR signaling pathway as therapeutic targets for sarcoma patients, Cancer Biol. Med., 13, 260–268.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Kaprin, A. D., Starinskiy, V. V., and Petrova, G. V. (2018) 2016 Malignancy Prevalence in Russia (Morbidity and Mortality) [in Russian], Moscow P. A. Gertsen Research Institute of Oncology, Branch of the National Medical Research Radiology Center, Ministry of Health of Russian Federation, Moscow.

    Google Scholar 

  15. Siegel, R. L., Miller, K. D., and Jemal, A. (2018) Cancer statistics, CA Cancer J. Clin., 68, 7–30.

    Article  PubMed  Google Scholar 

  16. Svatek, R. S., Hollenbeck, B. K., Holmang, S., Lee, R., Kim, S. P., Stenzl, A., and Lotan, Y. (2014) The economics of bladder cancer: costs and considerations of caring for this disease, Eur. Urol., 66, 253–262.

    Article  PubMed  Google Scholar 

  17. Knowles, M. A., and Hurst, C. D. (2015) Molecular biolo–gy of bladder cancer: new insights into pathogenesis and clinical diversity, Nat. Rev. Cancer, 15, 25–41.

    Article  PubMed  CAS  Google Scholar 

  18. Mikhaylenko, D. S., and Nemtsova, M. V. (2016) Point somatic mutations in developing stomach cancer: key carcinogenesis events, diagnostic markers and therapeutic targets, Urologiya, 1, 100–105.

    Google Scholar 

  19. Knowles, M. A., and Hurst, C. D. (2015) Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity, Nat. Rev. Cancer, 15, 25–41.

    Article  PubMed  CAS  Google Scholar 

  20. Del Piccolo, N., Placone, J., and Hristova, K. (2015) Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization, Biophys. J., 108, 272–278.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Di Martino, E., Kelly, G., Roulson, J. A., and Knowles, M. A. (2015) Alterations of cell–cell and cell–matrix adhesion in urothelial cells: an oncogenic mechanism for mutant FGFR3, Mol. Cancer Res., 13, 138–148.

    Article  PubMed  CAS  Google Scholar 

  22. Rivera, B., Gayden, T., Carrot–Zhang, J., Nadaf, J., Boshari, T., Faury, D., Zeinieh, M., Blanc, R., Burk, D. L., Fahiminiya, S., Bareke, E., Schuller, U., Monoranu, C. M., Strater, R., Kerl, K., Niederstadt, T., Kurlemann, G., Ellezam, B., Michalak, Z., Thom, M., Lockhart, P. J., Leventer, R. J., Ohm, M., MacGregor, D., Jones, D., Karamchandani, J., Greenwood, C. M., Berghuis, A. M., Bens, S., Siebert, R., Zakrzewska, M., Liberski, P. P., Zakrzewski, K., Sisodiya, S. M., Paulus, W., Albrecht, S., Hasselblatt, M., Jabado, N., Foulkes, W. D., and Majewski, J. (2016) Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors, Acta Neuropathol., 131, 847–863.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Gallo, L. H., Nelson, K. N., Meyer, A. N., and Donoghue, D. J. (2015) Functions of fibroblast growth factor receptors in cancer defined by novel translocations and mutations, Cytokine Growth Factor Rev., 26, 425–449.

    Article  PubMed  CAS  Google Scholar 

  24. Hallinan, N., Finn, S., Cuffe, S., Rafee, S., Byrne, K., and Gately, K. (2016) Targeting the fibroblast growth factor receptor family in cancer, Cancer Treat. Rev., 46, 51–62.

    Article  PubMed  CAS  Google Scholar 

  25. Babina, I. S., and Turner, N. C. (2017) Advances and challenges in targeting FGFR signaling in cancer, Nat. Rev. Cancer, 17, 318–332.

    Article  PubMed  CAS  Google Scholar 

  26. Tanner, Y., and Grose, R. P. (2016) Dysregulating FGF signalling in neoplastic disorders, Semin. Cell Dev. Biol., 53, 126–135.

    Article  PubMed  CAS  Google Scholar 

  27. Weinstein, J. N., Akbani, R., Broom, B. M., Wang, W., Verhaak, R. G., McConkey, D., Lerner, S., Morgan, M., Creighton, C. J., Smith, C., Cherniack, A. D., Kim, J., Sekhar, P. C., Noble, M. S., Al–Ahmadie, H. A., Reuter, V. E., Rosenberg, J. E., Bajorin, D. F., Bochner, B. H., Solit, D. B., et al. (2014) Comprehensive molecular characterization of urothelial bladder carcinoma, Nature, 507, 315–322.

    Article  CAS  Google Scholar 

  28. Guo, G., Sun, X., Chen, C., Wu, S., Huang, P., Li, Z., Dean, M., Huang, Y., Jia, W., Zhou, Q., Tang, A., Yang, Z., Li, X., Song, P., Zhao, X., Ye, R., Zhang, S., Lin, Z., Qi, M., Wan, S., Xie, L., Fan, F., Nickerson, M. L., Zou, X., Hu, X., Xing, L., Lv, Z., Mei, H., Gao, S., Liang, C., Gao, Z., Lu, J., Yu, Y., Liu, C., Li, L., Fang, X., Jiang, Z., Yang, J., Li, C., Zhao, X., Chen, J., Zhang, F., Lai, Y., Lin, Z., Zhou, F., Chen, H., Chan, H. C., Tsang, S., Theodorescu, D., Li, Y., Zhang, X., Wang, J., Yang, H., Gui, Y., Wang, J., and Cai, Z. (2013) Whole–genome and whole–exome sequencing of bladder cancer identifies fre–quent alterations in genes involved in sister chromatid cohesion and segregation, Nat. Genet., 45, 1459–1463.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Nakanishi, Y., Akiyama, N., Tsukaguchi, T., Fujii, T., Satoh, Y., Ishii, N., and Aoki, M. (2015) Mechanism of oncogenic signal activation by the novel fusion kinase FGFR3–BAIAP2L1, Mol. Cancer Ther., 14, 704–712.

    Article  PubMed  CAS  Google Scholar 

  30. Katoh, M. (2016) FGFR inhibitors: effects on cancer cells, tumor microenvironment and whole–body homeostasis (review), Int. J. Mol. Med., 38, 3–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Arai, Y., Totoki, Y., Hosoda, F., Shirota, T., Hama, N., Nakamura, H., Ojima, H., Furuta, K., Shimada, K., Okusaka, T., Kosuge, T., and Shibata, T. (2014) Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma, Hepatology, 5, 1427–1434.

    Article  CAS  Google Scholar 

  32. Fischbach, A., Rogler, A., Erber, R., Stoehr, R., Poulsom, R., Heidenreich, A., Schneevoigt, B. S., Hauke, S., Hartmann, A., Knuechel, R., Veeck, J., and Gaisa, N. T. (2015) Fibroblast growth factor receptor (FGFR) gene amplifications are rare events in bladder cancer, Histopathology, 66, 639–649.

    Article  PubMed  Google Scholar 

  33. Ross, J. S., Wang, K., Al–Rohil, R. N., Nazeer, T., Sheehan, C. E., Otto, G. A., He, J., Palmer, G., Yelensky, R., Lipson, D., Ali, S., Balasubramanian, S., Curran, J. A., Garcia, L., Mahoney, K., Downing, S. R., Hawryluk, M., Miller, V. A., and Stephens, P. J. (2013) Advanced urothelial carcinoma: next generation sequencing reveals diverse genomic alterations and targets of therapy, Mod. Pathol., 27, 271–280.

    Article  PubMed  CAS  Google Scholar 

  34. Cheng, T., Roth, B., Choi, W., Black, P. C., Dinney, C., and McConkey, D. J. (2013) Fibroblast growth factor receptors–1 and–3 play distinct roles in the regulation of bladder cancer growth and metastasis: implications for therapeutic targeting, PLoS One, 8, e57284.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Andre, F., Bachelot, T., Campone, M., Dalenc, F., Perez–Garcia, J. M., Hurvitz, S. A., Turner, N., Rugo, H., Smith, J. W., Deudon, S., Shi, M., Zhang, Y., Kay, A., Porta, D. G., Yovine, A., and Baselga, J. (2013) Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer, Clin. Cancer Res., 19, 3693–3702.

    Article  PubMed  CAS  Google Scholar 

  36. Kim, S., Dubrovska, A., Salamone, R. J., Walker, J. R., Grandinetti, K. B., Bonamy, G. M., Orth, A. P., Elliott, J., Porta, D. G., Garcia–Echeverria, C., and Reddy, V. A. (2013) FGFR2 promotes breast tumorigenicity through maintenance of breast tumor–initiating cells, PLoS One, 8, e51671.

    Google Scholar 

  37. Andre, F., and Cortes, J. (2015) Rationale for targeting fibroblast growth factor receptor signaling in breast cancer, Breast Cancer Res. Treat., 150, 1–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Neuzillet, Y., Van Rhijn, B. W., Prigoda, N. L., Bapat, B., Liu, L., Bostrom, P. J., Fleshner, N. E., Gallie, B. L., Zlotta, A. R., Jewett, M. A., and van der Kwast, T. H. (2014) FGFR3 mutations, but not FGFR3 expression and FGFR3 copy–number variations, are associated with favorable non–muscle invasive bladder cancer, Virchows Arch., 465, 207–213.

    Article  PubMed  CAS  Google Scholar 

  39. Guancial, E. A., Werner, L., Bellmunt, J., Bamias, A., Choueiri, T. K., Ross, R., Schutz, F. A., Park, R. S., Brien, R. J., Hirsch, M. S., Barletta, J. A., Berman, D. M., Lis, R., Loda, M., Stack, E. C., Garraway, L. A., Riester, M., Michor, F., Kantoff, P. W., and Rosenberg, J. E. (2014) FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder, Cancer Med., 3, 835–844.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Parker, B. C., Annala, M. J., Cogdell, D. E., Granberg, K. J., Sun, Y., Ji, P., Li, X., Gumin, J., Zheng, H., Hu, L., Yli–Harja, O., Haapasalo, H., Visakorpi, T., Liu, X., Liu, C. G., Sawaya, R., Fuller, G. N., Chen, K., Lang, F. F., Nykter, M., and Zhang, W. (2013) The tumorigenic FGFR3–TACC3 gene fusion escapes miR–99a regulation in glioblastoma, J. Clin. Invest., 123, 855–865.

    PubMed  PubMed Central  CAS  Google Scholar 

  41. Blick, C., Ramachandran, A., Wigfield, S., McCormick, R., Jubb, A., Buffa, F. M., Turley, H., Knowles, M. A., Cranston, D., Catto, J., and Harris, A. L. (2013) Hypoxia regulates FGFR3 expression via HIF–1alpha and miR–100 and contributes to cell survival in non–muscle invasive bladder cancer, Br. J. Cancer, 109, 50–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Sfakianos, J. P., Cha, E. K., Iyer, G., Scott, S. N., Zabor, E. C., Shah, R. H., Ren, Q., Bagrodia, A., Kim, P. H., Hakimi, A. A., Ostrovnaya, I., Ramirez, R., Hanrahan, A. J., Desai, N. B., Sun, A., Pinciroli, P., Rosenberg, J. E., Dalbagni, G., Schultz, N., Bajorin, D. F., Reuter, V. E., Berger, M. F., Bochner, B. H., Al–Ahmadie, H. A., Solit, D. B., and Coleman, J. A. (2015) Genomic characterization of upper tract urothelial carcinoma, Eur. Urol., 68, 970–977.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Spiegelberg, C., Giedl, J., Gaisa, N. T., Rogler, A., Riener, M. O., Filbeck, T., Burger, M., Ruemmele, P., Hartmann, A., and Stoehr, R. (2014) Frequency of activating muta–tions in FGFR2 exon 7 in bladder tumors from patients with early–onset and regular–onset disease, Int. J. Clin. Exp. Pathol., 7, 1708–1713.

    PubMed  PubMed Central  Google Scholar 

  44. Bertz, S., Abee, C., Schwarz–Furlan, S., Alfer, J., Hofstadter, F., Stoehr, R., Hartmann, A., and Gaumann, A. K. (2014) Increased angiogenesis and FGFR protein expression indicate a favorable prognosis in bladder cancer, Virchows Arch., 465, 687–695.

    Article  PubMed  CAS  Google Scholar 

  45. Giacomini, A., Chiodelli, P., Matarazzo, S., Rusnati, M., Presta, M., and Ronca, R. (2016) Blocking the FGF/FGFR system as a “two–compartment” antiangiogenic/antitumor approach in cancer therapy, Pharmacol. Res., 107, 172–185.

    Article  PubMed  CAS  Google Scholar 

  46. Katoh, M. (2016) Therapeutics targeting FGF signaling network in human diseases, Trends Pharmacol. Sci., 37, 1081–1096.

    Article  PubMed  CAS  Google Scholar 

  47. Di Meo, A., Bartlett, J., Cheng, Y., Pasic, M. D., and Yousef, G. M. (2017) Liquid biopsy: a step forward towards precision medicine in urologic malignancies, Mol. Cancer, 16, 80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Noel, N., Couteau, J., Maillet, G., Gobet, F., Aloisio, F., Minier, C., and Pfister, C. (2015) TP53 and FGFR3 gene mutation assessment in urine: pilot study for bladder cancer diagnosis, Anticancer Res., 35, 4915–4921.

    PubMed  CAS  Google Scholar 

  49. Critelli, R., Fasanelli, F., Oderda, M., Polidoro, S., Assumma, M. B., Viberti, C., Preto, M., Gontero, P., Cucchiarale, G., Lurkin, I., Zwarthoff, E. C., Vineis, P., Sacerdote, C., Matullo, G., and Naccarati, A. (2016) Detection of multiple mutations in urinary exfoliated cells from male bladder cancer patients at diagnosis and during follow–up, Oncotarget, 7, 7435–67448.

    Article  Google Scholar 

  50. Togneri, F. S., Ward, D. G., Foster, J. M., Devall, A. J., Wojtowicz, P., Alyas, S., Vasques, F. R., Oumie, A., James, N. D., Cheng, K. K., Zeegers, M. P., Deshmukh, N., Sullivan, B., Taniere, P., Spink, K. G., McMullan, D. J., Griffiths, M., and Bryan, R. T. (2016) Genomic complexity of urothelial bladder cancer revealed in urinary cfDNA, Eur. J. Hum. Genet., 24, 1167–1174.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Karnes, R. J., Fernandez, C. A., and Shuber, A. P. (2012) A noninvasive multianalyte urine–based diagnostic assay for urothelial cancer of the bladder in the evaluation of hematuria, Mayo Clin. Proc., 87, 835–842.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Van Kessel, K. E., Beukers, W., Lurkin, I., Ziel–van der Made, A., van der Keur, K. A., Boormans, J. L., Dyrskjot, L., Marquez, M., Orntoft, T. F., Real, F. X., Segersten, U., Malats, N., Malmstrom, P. U., van Criekinge, W., and Zwarthoff, E. C. (2017) Validation of a DNA methylation–mutation urine assay to select patients with hematuria for cystoscopy, J. Urol., 197, 590–595.

    Article  PubMed  CAS  Google Scholar 

  53. Descotes, F., Kara, N., Decaussin–Petrucci, M., Piaton, E., Geiguer, F., Rodriguez–Lafrasse, C., Terrier, J. E., Lopez, J., and Ruffion, A. (2017) Non–invasive prediction of recurrence in bladder cancer by detecting somatic TERT promoter mutations in urine, Br. J. Cancer, 117, 583–587.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Pivovarcikova, K., Pitra, T., Vanecek, T., Alaghehbandan, R., Gomolcakova, B., Ondic, O., Peckova, K., Rotterova, P., Hora, M., Dusek, M., Michal, M., and Hes, O. (2016) Comparative study of TERT gene mutation analysis on voided liquid–based urine cytology and paraffin–embedded tumorous tissue, Ann. Diagn. Pathol., 24, 7–10.

    Article  PubMed  Google Scholar 

  55. Ward, D. G., and Bryan, R. T. (2017) Liquid biopsies for bladder cancer, Transl. Androl. Urol., 6, 331–335.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ross, J. S., Wang, K., Khaira, D., Ali, S. M., Fisher, H. A., Mian, B., Nazeer, T., Elvin, J. A., Palma, N., Yelensky, R., Lipson, D., Miller, V. A., Stephens, P. J., Subbiah, V., and Pal, S. K. (2016) Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations, Cancer, 122, 702–711.

    Article  PubMed  CAS  Google Scholar 

  57. Hedegaard, J., Lamy, P., Nordentoft, I., Algaba, F., Hoyer, S., Ulhoi, B. P., Vang, S., Reinert, T., Hermann, G. G., Mogensen, K., Thomsen, M. B., Nielsen, M. M., Marquez, M., Segersten, U., Aine, M., Hoglund, M., Birkenkamp–Demtroder, K., Fristrup, N., Borre, M., Hartmann, A., Stohr, R., Wach, S., Keck, B., Seitz, A. K., Nawroth, R., Maurer, T., Tulic, C., Simic, T., Junker, K., Horstmann, M., Harving, N., Petersen, A. C., Calle, M. L., Steyerberg, E. W., Beukers, W., van Kessel, K. E. M., Jensen, J. B., Pedersen, J. S., Malmstrom, P. U., Malats, N., Real, F. X., Zwarthoff, E. C., Orntoft, T. F., and Dyrskjot, L. (2016) Comprehensive transcriptional analysis of early–stage urothelial carcinoma, Cancer Cell, 30, 27–42.

    Article  PubMed  CAS  Google Scholar 

  58. Meeks, J. J., Carniero, B. A., Pai, S. G., Oberlin, D. T., Rademaker, A., Fedorchak, K., Balasubramanian, S., Elvin, J., Beaubier, N., and Giles, F. J. (2016) Genomic characterization of high–risk non–muscle invasive bladder cancer, Oncotarget, 7, 75176–75184.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Scott, S. N., Ostrovnaya, I., Lin, C. M., Bouvier, N., Bochner, B. H., Iyer, G., Solit, D., Berger, M. F., and Lin, O. (2017) Next–generation sequencing of urine specimens: a novel platform for genomic analysis in patients with non–muscle–invasive urothelial carcinoma treated with Bacille Calmette–Guerin, Cancer Cytopathol., 125, 416–426.

    Article  PubMed  CAS  Google Scholar 

  60. Ojha, J., Ayres, J., Secreto, C., Tschumper, R., Rabe, K., van Dyke, D., Slager, S., Shanafelt, T., Fonseca, R., Kay, N. E., and Braggio, E. (2015) Deep sequencing identifies genetic heterogeneity and recurrent convergent evolution in chronic lymphocytic leukemia, Blood, 125, 492–498.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Fisher, R., Horswell, S., Rowan, A., Salm, M. P., de Bruin, E. C., Gulati, S., McGranahan, N., Stares, M., Gerlinger, M., Varela, I., Crockford, A., Favero, F., Quidville, V., Andre, F., Navas, C., Gronroos, E., Nicol, D., Hazell, S., Hrouda, D., O’Brien, T., Matthews, N., Phillimore, B., Begum, S., Rabinowitz, A., Biggs, J., Bates, P. A., McDonald, N. Q., Stamp, G., Spencer–Dene, B., Hsieh, J. J., Xu, J., Pickering, L., Gore, M., Larkin, J., and Swanton, C. (2014) Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution, Genome Biol., 15, 433.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Aragon–Ching, J. B., and Trump, D. L. (2016) Systematic therapy in muscle–invasive and metastatic bladder cancer: current trends and future promises, Future Oncol., 12, 2049–2058.

    Article  PubMed  CAS  Google Scholar 

  63. Moss, T. J., Qi, Y., Xi, L., Peng, B., Kim, T. B., Ezzedine, N. E., Mosqueda, M. E., Guo, C. C., Czerniak, B. A., Ittmann, M., Wheeler, D. A., Lerner, S. P., and Matin, S. F. (2017) Comprehensive genomic characterization of upper tract urothelial carcinoma, Eur. Urol., 72, 641–649.

    Article  PubMed  CAS  Google Scholar 

  64. Acar, O., Ozkurt, E., Demir, G., Sarac, H., Alkan, C., Esen, T., Somel, M., and Lack, N. A. (2015) Determining the origin of synchronous multifocal bladder cancer by exome sequencing, BMC Cancer, 15, 871.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Pouessel, D., Neuzillet, Y., Mertens, L. S., van der Heijden, M. S., de Jong, J., Sanders, J., Peters, D., Leroy, K., Manceau, A., Maille, P., Soyeux, P., Moktefi, A., Semprez, F., Vordos, D., de la Taille, A., Hurst, C. D., Tomlinson, D. C., Harnden, P., Bostrom, P. J., Mirtti, T., Horenblas, S., Loriot, Y., Houede, N., Chevreau, C., Beuzeboc, P., Shariat, S. F., Sagalowsky, A. I., Ashfaq, R., Burger, M., Jewett, M. A., Zlotta, A. R., Broeks, A., Bapat, B., Knowles, M. A., Lotan, Y., van der Kwast, T. H., Culine, S., Allory, Y., and van Rhijn, B. W. (2016) Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti–FGFR3 treatment, Ann. Oncol., 27, 1311–1316.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Ho, H. K., Yeo, A. H., Kang, T. S., and Chua, B. T. (2014) Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations, Drug Discov. Today, 19, 51–62.

    Article  PubMed  CAS  Google Scholar 

  67. Hierro, C., Rodon, J., and Tabernero, J. (2015) Fibroblast growth factor (FGF) receptor/FGF inhibitors: novel targets and strategies for optimization of response of solid tumors, Semin. Oncol., 42, 801–819.

    Article  PubMed  CAS  Google Scholar 

  68. Milowsky, M. I., Dittrich, C., Duran, I., Jagdev, S., Millard, F. E., Sweeney, C. J., Bajorin, D., Cerbone, L., Quinn, D. I., Stadler, W. M., Rosenberg, J. E., Lochheed, M., Sen, P., Squires, M., Shi, M., and Sternberg, C. N. (2014) Phase II trial of dovitinib in patients with progressive FGFR3–mutated or FGFR3 wild–type advanced urothelial carcinoma, Eur. J. Cancer, 50, 3145–3152.

    Article  PubMed  CAS  Google Scholar 

  69. Shah, D. R., Shah, R. R., and Morganroth, J. (2013) Tyrosine kinase inhibitors: their on–target toxicities as potential indicators of efficacy, Drug Saf., 36, 413–426.

    Article  PubMed  CAS  Google Scholar 

  70. Tabernero, J., Bahleda, R., Dienstmann, R., Infante, J. R., Mita, A., Italiano, A., Calvo, E., Moreno, V., Adamo, B., Gazzah, A., Zhong, B., Platero, S. J., Smit, J. W., Stuyckens, K., Chatterjee–Kishore, M., Rodon, J., Peddareddigari, V., Luo, F. R., and Soria, J. C. (2015) 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., 33, 3401–3408.

    Article  PubMed  CAS  Google Scholar 

  71. Jager, W., Xue, H., Hayashi, T., Janssen, C., Awrey, S., Wyatt, A. W., Anderson, S., Moskalev, I., Haegert, A., Alshalalfa, M., Erho, N., Davicioni, E., Fazli, L., Li, E., Collins, C., Wang, Y., and Black, P. C. (2015) Patient–derived bladder cancer xenografts in the preclinical development of novel targeted therapies, Oncotarget, 6, 21522–21532.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Harding, T. C., Long, L., Palencia, S., Zhang, H., Sadra, A., Hestir, K., Patil, N., Levin, A., Hsu, A. W., Charych, D., Brennan, T., Zanghi, J., Halenbeck, R., Marshall, S. A., Qin, M., Doberstein, S. K., Hollenbaugh, D., Kavanaugh, W. M., Williams, L. T., and Baker, K. P. (2013) Blockade of nonhormonal fibroblast growth factor by FP–1039 inhibits growth of multiple types of cancer, Sci. Transl. Med., 5, Suppl. 39.

    Google Scholar 

  73. Presta, M., Chiodelli, P., Giacomini, A., Rusnati, M., and Ronca, R. (2017) Fibroblast growth factors (FGFs) in can–cer: FGF traps as a new therapeutic approach, Pharmacol. Ther., 179, 171–187.

    Article  PubMed  CAS  Google Scholar 

  74. Acquaviva, J., He, S., Zhang, C., Jimenez, J.–P., Nagai, M., Sang, J., Sequeira, M., Smith, D. L., Ogavva, L. S., Takayo, I., Tatsuta, N., Knowles, M. A., Bates, R. C., and Proia, D. A. (2014) FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism, Mol. Cancer Res., 12, 1042–1054.

    Article  PubMed  CAS  Google Scholar 

  75. Carneiro, B. A., Meeks, J. J., Kuzel, T. M., Scaranti, M., Abdulkadir, S. A., and Giles, F. J. (2015) Emerging therapeutic targets in bladder cancer, Cancer Treat. Rev., 41, 170–178.

    Article  PubMed  CAS  Google Scholar 

  76. Yashiro, M., and Matsuoka, T. (2016) Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer, World J. Gastroenterol., 22, 2415–2423.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Chang, J., Liu, X., Wang, S., Zhang, Z., Wu, Z., Zhang, X., and Li, J. (2014) Prognostic value of FGFR gene amplification in patients with different types of cancer: a systematic review and meta–analysis, PLoS One, 9, e105524.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Herrera–Abreu, M. T., Pearson, A., Campbell, J., Shnyder, S. D., Knowles, M. A., Ashworth, A., and Turner, N. C. (2013) Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3–mutant cancer, Cancer Discov., 3, 1058–1071.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Wang, J., Mikse, O., Liao, R. G., Li, Y., Tan, L., Janne, P. A., Gray, N. S., Wong, K. K., and Hammerman, P. S. (2015) Ligand–associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3–dependent cancer cells, Oncogene, 34, 2167–2177.

    Article  PubMed  CAS  Google Scholar 

  80. Chell, V., Balmanno, K., Little, A. S., Wilson, M., Andrews, S., Blockley, L., Hampson, M., Gavine, P. R., and Cook, S. J. (2013) Tumor cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance, Oncogene, 32, 3059–3070.

    Article  PubMed  CAS  Google Scholar 

  81. Bunney, T. D., Wan, S., Thiyagarajan, N., Sutto, L., Williams, S. V., Ashford, P., Koss, H., Knowles, M. A., Gervasio, F. L., Coveney, P. V., and Katan, M. (2015) The effect of mutations on drug sensitivity and kinase activity of fibroblast growth factor receptors: a combined experimental and theoretical study, EBioMedicine, 2, 194–204.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Abbosh, P. H., McConkey, D. J., and Plimack, E. R. (2015) Targeting signaling transduction pathways in bladder cancer, Curr. Oncol. Rep., 17, 58.

    Article  PubMed  CAS  Google Scholar 

  83. Van Kessel, K. E., Zuiverloon, T. C., Alberts, A. R., Boormans, J. L., and Zwarthoff, E. C. (2015) Targeted therapies in bladder cancer: an overview of in vivo research, Nat. Rev. Urol., 12, 681–694.

    Article  PubMed  CAS  Google Scholar 

  84. Fedyanin, M. Yu., Khmel’kova, D. N., Serebriyskaya, T. S., Nikol’skaya, T. A., and Tyulyandin, S. A. (2015) Perspectives of therapeutic intervention in FGFR–linked signaling pathway, Uspekhi Mol. Onkol., 1, 27–38.

    Article  Google Scholar 

  85. Chae, Y. K., Ranganath, K., Hammerman, P. S., Vaklavas, C., Mohindra, N., Kalyan, A., Matsangou, M., Costa, R., Carneiro, B., Villaflor, V. M., Cristofanilli, M., and Giles, F. J. (2017) Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application, Oncotarget, 8, 16052–16074.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Sechenov First Moscow State Medical University, Institute of Molecular Medicine, 119991, Moscow, Russia

    D. S. Mikhaylenko, D. V. Zaletaev & M. V. Nemtsova

  2. Lopatkin Research Institute of Urology and Interventional Radiology, Branch of the National Medical Research Center of Radiology, Ministry of Health of Russian Federation, 105425, Moscow, Russia

    D. S. Mikhaylenko & B. Y. Alekseev

  3. Research Centre for Medical Genetics, 115478, Moscow, Russia

    D. S. Mikhaylenko & M. V. Nemtsova

  4. Institute of Genetics and Cytology, Belorussian National Academy of Sciences, 220072, Minsk, Belarus

    R. I. Goncharova

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  1. D. S. Mikhaylenko
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Correspondence to D. S. Mikhaylenko.

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Original Russian Text © D. S. Mikhaylenko, B. Y. Alekseev, D. V. Zaletaev, R. I. Goncharova, M. V. Nemtsova, 2018, published in Biokhimiya, 2018, Vol. 83, No. 8, pp. 1173–1189.

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Mikhaylenko, D.S., Alekseev, B.Y., Zaletaev, D.V. et al. Structural Alterations in Human Fibroblast Growth Factor Receptors in Carcinogenesis. Biochemistry Moscow 83, 930–943 (2018). https://doi.org/10.1134/S0006297918080059

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