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Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance - British Journal of Cancer

  • ️Roychowdhury, Sameek
  • ️Thu Dec 03 2020

References

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

    CAS  PubMed  Google Scholar 

  2. Ornitz, D. M. & Itoh, N. The fibroblast growth factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 4, 215–266 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Helsten, T., Elkin, S., Arthur, E., Tomson, B. N., Carter, J. & Kurzrock, R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin. Cancer Res. 22, 259–267 (2016).

    CAS  PubMed  Google Scholar 

  4. Imamura, T. Physiological functions and underlying mechanisms of fibroblast growth factor (FGF) family members: recent findings and implications for their pharmacological application. Biol. Pharm. Bull. 37, 1081–1089 (2014).

    CAS  PubMed  Google Scholar 

  5. Qin, A., Johnson, A., Ross, J. S., Miller, V. A., Ali, S. M., Schrock, A. B. & Gadgeel, S. M. Detection of known and novel FGFR fusions in non-small cell lung cancer by comprehensive genomic profiling. J. Thorac. Oncol. 14, 54–62 (2019).

    CAS  PubMed  Google Scholar 

  6. Tiong, K. H., Mah, L. Y. & Leong, C. O. Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis 18, 1447–1468 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sobhani, N., Ianza, A., D’Angelo, A., Roviello, G., Giudici, F., Bortul, M., Zanconati, F., Bottin, C. & Generali, D. Current status of fibroblast growth factor receptor-targeted therapies in breast cancer. Cells 7, 76 (2018).

    PubMed Central  Google Scholar 

  8. Göke, F., Franzen, A., Hinz, T. K., Marek, L. A., Yoon, P., Sharma, R. et al. FGFR1 expression levels predict BGJ398 sensitivity of FGFR1-dependent head and neck squamous cell cancers. Clin. Cancer Res. 21, 4356–4364 (2015).

    PubMed  PubMed Central  Google Scholar 

  9. Göke, F., Bode, M., Franzen, A., Kirsten, R., Goltz, D., Göke, A. et al. Fibroblast growth factor receptor 1 amplification is a common event in squamous cell carcinoma of the head and neck. Mod. Pathol. 26, 1298–1306 (2013).

    PubMed  Google Scholar 

  10. Loriot, Y., Necchi, A., Park, S. H., Garcia-Donas, J., Huddart, R., Burgess, E. et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N. Engl. J. Med. 381, 338–348 (2019).

    CAS  PubMed  Google Scholar 

  11. Abou-Alfa, G. K., Sahai, V., Hollebecque, A., Vaccaro, G., Melisi, D., Al-Rajabi, R. et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 21, 671–684 (2020).

    CAS  PubMed  Google Scholar 

  12. Krook, M. A., Silverman, I. M., Murugesan, K., Ernst, G., Reeser, J., Wing, M. et al. Pan-cancer analysis of FGFR1-3 genomic alterations to reveal a complex molecular landscape. J. Clin. Oncol. 38, 3620 (2020).

    Google Scholar 

  13. Forbes, S. A., Beare, D., Gunasekaran, P., Leung, K., Bindal, N., Boutselakis, H. et al. COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acids Res. 43, D805–D811 (2015).

    CAS  PubMed  Google Scholar 

  14. Lew, E. D., Furdui, C. M., Anderson, K. S. & Schlessinger, J. The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations. Sci. Signal. 2, ra6 (2009).

    PubMed  PubMed Central  Google Scholar 

  15. Hart, K. C., Robertson, S. C., Kanemitsu, M. Y., Meyer, A. N., Tynan, J. A. & Donoghue, D. J. Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 19, 3309–3320 (2000).

    CAS  PubMed  Google Scholar 

  16. AACR Project GENIE. Powering precision medicine through an international consortium. Cancer Discov. 7, 818–831 (2017).

  17. André, F. & Cortés, J. Rationale for targeting fibroblast growth factor receptor signaling in breast cancer. Breast Cancer Res. Treat. 150, 1–8 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. Dutt, A., Salvesen, H. B., Chen, T. H., Ramos, A. H., Onofrio, R. C., Hatton, C. et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl Acad. Sci. USA 105, 8713–8717 (2008).

    CAS  PubMed  Google Scholar 

  20. Greenman, C., Stephens, P., Smith, R., Dalgliesh, G. L., Hunter, C., Bignell, G. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hernández, S., López-Knowles, E., Lloreta, J., Kogevinas, M., Amorós, A., Tardón, A. et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J. Clin. Oncol. 24, 3664–3671 (2006).

    PubMed  Google Scholar 

  22. d’Avis, P. Y., Robertson, S. C., Meyer, A. N., Bardwell, W. M., Webster, M. K. & Donoghue, D. J. Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I. Cell Growth Differ. 9, 71–78 (1998).

    PubMed  Google Scholar 

  23. Rosty, C., Aubriot, M. H., Cappellen, D., Bourdin, J., Cartier, I., Thiery, J. P. et al. Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation. Mol. Cancer 4, 15 (2005).

    PubMed  PubMed Central  Google Scholar 

  24. JGt, Taylor, Cheuk, A. T., Tsang, P. S., Chung, J. Y., Song, Y. K., Desai, K. et al. Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J. Clin. Invest. 119, 3395–3407 (2009).

    Google Scholar 

  25. Tang, S., Hao, Y., Yuan, Y., Liu, R. & Chen, Q. Role of fibroblast growth factor receptor 4 in cancer. Cancer Sci. 109, 3024–3031 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ruhe, J. E., Streit, S., Hart, S., Wong, C. H., Specht, K., Knyazev, P. et al. Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines. Cancer Res. 67, 11368–11376 (2007).

    CAS  PubMed  Google Scholar 

  27. Roidl, A., Foo, P., Wong, W., Mann, C., Bechtold, S., Berger, H. J., Streit, S., Ruhe, J. E., Hart, S., Ullrich, A. & Ho, H. K. The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells. Oncogene 29, 1543–1552 (2010).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nat. Rev. Cancer 7, 233–245 (2007).

    CAS  PubMed  Google Scholar 

  30. Doebele, R. C., Drilon, A., Paz-Ares, L., Siena, S., Shaw, A. T., Farago, A. F. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 21, 271–282 (2020).

    CAS  PubMed  Google Scholar 

  31. Drilon, A., Laetsch, T. W., Kummar, S., DuBois, S. G., Lassen, U. N., Demetri, G. D. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Gettinger, S. N., Bazhenova, L. A., Langer, C. J., Salgia, R., Gold, K. A., Rosell, R. et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol. 17, 1683–1696 (2016).

    CAS  Google Scholar 

  33. O’Brien, S. G., Guilhot, F., Larson, R. A., Gathmann, I., Baccarani, M., Cervantes, F. et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 348, 994–1004 (2003).

    PubMed  Google Scholar 

  34. Peters, S., Camidge, D. R., Shaw, A. T., Gadgeel, S., Ahn, J. S., Kim, D. W. et al. Alectinib versus Crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 377, 829–838 (2017).

    CAS  PubMed  Google Scholar 

  35. Wu, Y. M., Su, F., Kalyana-Sundaram, S., Khazanov, N., Ateeq, B., Cao, X. et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 3, 636–647 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Singh, D., Chan, J. M., Zoppoli, P., Niola, F., Sullivan, R., Castano, A. et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337, 1231–1235 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Katoh, M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat. Rev. Clin. Oncol. 16, 105–122 (2019).

    CAS  PubMed  Google Scholar 

  38. Ray, M. E., Yang, Z. Q., Albertson, D., Kleer, C. G., Washburn, J. G., Macoska, J. A. & Ethier, S. P. Genomic and expression analysis of the 8p11–12 amplicon in human breast cancer cell lines. Cancer Res. 64, 40–47 (2004).

    CAS  PubMed  Google Scholar 

  39. Paik, P. K. & Rudin, C. M. Missing the mark in FGFR1-amplified squamous cell cancer of the lung. Cancer 122, 2938–2940 (2016).

    PubMed  Google Scholar 

  40. Ng, T. L., Yu, H., Smith, D. E., Boyle, T. A., York, E. R., Leedy, S. et al. Preselection of lung cancer cases using FGFR1 mRNA and gene copy number for treatment with ponatinib. Clin. Lung Cancer 20, e39–e51 (2019).

    CAS  PubMed  Google Scholar 

  41. Chesi, M., Nardini, E., Brents, L. A., Schrock, E., Ried, T., Kuehl, W. M. & Bergsagel, P. L. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat. Genet. 16, 260–264 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Richelda, R., Ronchetti, D., Baldini, L., Cro, L., Viggiano, L., Marzella, R. et al. A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. Blood 90, 4062–4070 (1997).

    CAS  PubMed  Google Scholar 

  43. Benayed, R., Offin, M., Mullaney, K., Sukhadia, P., Rios, K., Desmeules, P. et al. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden. Clin. Cancer Res. 25, 4712–4722 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Maher, C. A., Kumar-Sinha, C., Cao, X., Kalyana-Sundaram, S., Han, B., Jing, X. et al. Transcriptome sequencing to detect gene fusions in cancer. Nature 458, 97–101 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Reeser, J. W., Martin, D., Miya, J., Kautto, E. A., Lyon, E., Zhu, E. et al. Validation of a targeted RNA sequencing assay for kinase fusion detection in solid tumors. J. Mol. Diagn. 19, 682–696 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zheng, Z., Liebers, M., Zhelyazkova, B., Cao, Y., Panditi, D., Lynch, K. D. et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat. Med. 20, 1479–1484 (2014).

    CAS  PubMed  Google Scholar 

  47. Childress, M. A., Himmelberg, S. M., Chen, H., Deng, W., Davies, M. A. & Lovly, C. M. ALK fusion partners impact response to ALK inhibition: differential effects on sensitivity, cellular phenotypes, and biochemical properties. Mol. Cancer Res. 16, 1724 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Mouliere, F., Chandrananda, D., Piskorz, A. M., Moore, E. K., Morris, J., Ahlborn, L. B. et al. Enhanced detection of circulating tumor DNA by fragment size analysis. Sci. Transl. Med. 10, aat4921 (2018).

    Google Scholar 

  49. Moss, T. J., Ahnert, J. R., Oakley, H. D., Kahle, M., Karp, D. D., Pant, S. et al. Baseline cfDNA characteristics and evolution of cfDNA profile during treatment with selective FGFR inhibitor TAS-120. J. Clin. Oncol. 37, 3056 (2019).

    Google Scholar 

  50. Varghese, A. M., Patel, J. A. A., Janjigian, Y. Y., Meng, F., Selcuklu, S. D., Zimel, C. et al. Non-invasive detection of acquired resistance to FGFR inhibition in patients with cholangiocarcinoma harboring FGFR2 alterations. J. Clin. Oncol. 37, 4096 (2019).

    Google Scholar 

  51. Sharma, M., Schilero, C., Peereboom, D. M., Hobbs, B. P., Elson, P., Stevens, G. H. J. et al. Phase II study of Dovitinib in recurrent glioblastoma. J. Neurooncol. 144, 359–368 (2019).

    CAS  PubMed  Google Scholar 

  52. Gainor, J. F. & Chabner, B. A. Ponatinib: accelerated disapproval. Oncologist 20, 847–848 (2015).

    PubMed  PubMed Central  Google Scholar 

  53. Hibi, M., Kaneda, H., Tanizaki, J., Sakai, K., Togashi, Y., Terashima, M. et al. FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib. Cancer Sci. 107, 1667–1676 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Cha, Y., Kim, H.-P., Lim, Y., Han, S.-W., Song, S.-H. & Kim, T.-Y. FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro. Mol. Oncol. 12, 993–1003 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Mazzaferro, V., El-Rayes, B. F., Droz dit Busset, M., Cotsoglou, C., Harris, W. P., Damjanov, N. et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br. J. Cancer 120, 165–171 (2019).

    CAS  PubMed  Google Scholar 

  56. Thompson, P. A., Young, N. P., Stumpf, C. R., Eam, B., Goel, V. K., Chen, J. et al. Abstract B133: eFT226, a first in class inhibitor of eIF4A1, targets FGFR1/2 and HER2 driven cancers. Mol. Cancer Ther. 18, B133–B133 (2019).

    Google Scholar 

  57. Sun, Y., Niu, W., Du, F., Du, C., Li, S., Wang, J., Li, L., Wang, F., Hao, Y., Li, C. & Chi, Y. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J. Hematol. Oncol. 9, 105 (2016).

    PubMed  PubMed Central  Google Scholar 

  58. Wang, Y., Bao, H., Zhang, N., Wang, F., He, Y. & Wu, T. Preclinical evaluation of MAX-40279, a FLT3/FGFR dual kinase inhibitor for treatment of acute myeloid leukemia. Blood 132, 3997 (2018).

    Google Scholar 

  59. Kim, S. T., Jang, H. L., Lee, S. J., Lee, J., Choi, Y. L., Kim, K. M. et al. Pazopanib, a novel multitargeted kinase inhibitor, shows potent in vitro antitumor activity in gastric cancer cell lines with FGFR2 amplification. Mol. Cancer Ther. 13, 2527–2536 (2014).

    CAS  PubMed  Google Scholar 

  60. Holmström, T. H., Moilanen, A.-M., Ikonen, T., Björkman, M. L., Linnanen, T., Wohlfahrt, G. et al. ODM-203, a selective inhibitor of FGFR and VEGFR, shows strong antitumor activity, and induces antitumor immunity. Mol. Cancer Ther. 18, 28–38 (2019).

    PubMed  Google Scholar 

  61. Boisseau, W., Euskirchen, P., Mokhtari, K., Dehais, C., Touat, M., Hoang-Xuan, K. et al. Molecular profiling reclassifies adult astroblastoma into known and clinically distinct tumor entities with frequent mitogen-activated protein kinase pathway alterations. Oncologist 24, 1584–1592 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wu, D., Guo, M., Philips, M. A., Qu, L., Jiang, L., Li, J. et al. Crystal structure of the FGFR4/LY2874455 complex reveals insights into the Pan-FGFR selectivity of LY2874455. PLoS ONE 11, e0162491 (2016).

    PubMed  PubMed Central  Google Scholar 

  63. Perera, T. P. S., Jovcheva, E., Mevellec, L., Vialard, J., De Lange, D., Verhulst, T. et al. Discovery and pharmacological characterization of JNJ-42756493 (Erdafitinib), a functionally selective small-molecule FGFR family inhibitor. Mol. Cancer Ther. 16, 1010–1020 (2017).

    CAS  PubMed  Google Scholar 

  64. Tsimafeyeu, I., Ludes-Meyers, J., Stepanova, E., Daeyaert, F., Khochenkov, D., Joose, J.-B. et al. Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models. Eur. J. Cancer 61, 20–28 (2016).

    CAS  PubMed  Google Scholar 

  65. Fumarola, C., Bozza, N., Castelli, R., Ferlenghi, F., Marseglia, G., Lodola, A. et al. Expanding the arsenal of FGFR inhibitors: a novel chloroacetamide derivative as a new irreversible agent with anti-proliferative activity against FGFR1-amplified lung cancer cell lines. Front. Oncol. 9, 179 (2019).

    PubMed  PubMed Central  Google Scholar 

  66. Kalyukina, M., Yosaatmadja, Y., Middleditch, M. J., Patterson, A. V., Smaill, J. B. & Squire, C. J. TAS-120 cancer target binding: defining reactivity and revealing the first fibroblast growth factor receptor 1 (FGFR1) irreversible structure. ChemMedChem 14, 494–500 (2019).

    CAS  PubMed  Google Scholar 

  67. Dai, S., Zhou, Z., Chen, Z., Xu, G. & Chen, Y. Fibroblast growth factor receptors (FGFRs): structures and small molecule inhibitors. Cells. 8, 614 (2019).

    CAS  PubMed Central  Google Scholar 

  68. Bai, A., Meetze, K., Vo, N. Y., Kollipara, S., Mazsa, E. K., Winston, W. M. et al. GP369, an FGFR2-IIIb-specific antibody, exhibits potent antitumor activity against human cancers driven by activated FGFR2 signaling. Cancer Res. 70, 7630–7639 (2010).

    CAS  PubMed  Google Scholar 

  69. Sommer, A., Kopitz, C., Schatz, C. A., Nising, C. F., Mahlert, C., Lerchen, H. G. et al. Preclinical efficacy of the auristatin-based antibody-drug conjugate BAY 1187982 for the treatment of FGFR2-positive solid tumors. Cancer Res. 76, 6331–6339 (2016).

    CAS  PubMed  Google Scholar 

  70. Kim, S. B., Meric-Bernstam, F., Kalyan, A., Babich, A., Liu, R., Tanigawa, T. et al. First-in-human phase I study of aprutumab ixadotin, a fibroblast growth factor receptor 2 antibody-drug conjugate (BAY 1187982) in patients with advanced cancer. Target Oncol. 14, 591–601 (2019).

    PubMed  PubMed Central  Google Scholar 

  71. Catenacci, D. V., Tesfaye, A., Tejani, M., Cheung, E., Eisenberg, P., Scott, A. J. et al. Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT Phase III study design. Fut. Oncol. 15, 2073–2082 (2019).

    CAS  Google Scholar 

  72. Qing, J., Du, X., Chen, Y., Chan, P., Li, H., Wu, P. et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J. Clin. Invest. 119, 1216–1229 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Trudel, S., Bergsagel, P. L., Singhal, S., Niesvizky, R., Comenzo, R. L., Bensinger, W. I. et al. A phase I study of the safety and pharmacokinetics of escalating doses of MFGR1877S, a fibroblast growth factor receptor 3 (FGFR3) antibody, in patients with relapsed or refractory t(4;14)-positive multiple myeloma. Blood 120, 4029 (2012).

    Google Scholar 

  74. Odonnell, P., Goldman, J. W., Gordon, M. S., Shih, K., Choi, Y. J., Lu, D. et al. A phase I dose-escalation study of MFGR1877S, a human monoclonal anti-fibroblast growth factor receptor 3 (FGFR3) antibody, in patients (pts) with advanced solid tumors. Eur. J. Cancer 48, 191–192 (2012).

    Google Scholar 

  75. Moek, K. L., de Groot, D. J. A., de Vries, E. G. E. & Fehrmann, R. S. N. The antibody-drug conjugate target landscape across a broad range of tumour types. Ann. Oncol. 28, 3083–3091 (2017).

    CAS  PubMed  Google Scholar 

  76. Surguladze, D., Pennello, A., Ren, X., Mack, T., Rigby, A., Balderes, P. et al. LY3076226, a novel anti-FGFR3 antibody drug conjugate exhibits potent and durable anti-tumor activity in tumor models harboring FGFR3 mutations or fusions. Cancer Res. 79, 4835 (2019).

    Google Scholar 

  77. Bellmunt, J., Picus, J., Kohli, M., Arriaga, Y. E., Milowsky, M. I., Currie, G. et al. FIERCE-21: phase 1b/2 study of docetaxel + b-701, a selective inhibitor of FGFR3, in relapsed or refractory (R/R) metastatic urothelial carcinoma (mUCC). J. Clin. Oncol. 36, 4534 (2018).

    Google Scholar 

  78. Siefker-Radtke, A. O., Currie, G., Abella, E., Vaena, D. A., Kalebasty, A. R., Curigliano, G. et al. FIERCE-22: Clinical activity of vofatamab (V) a FGFR3 selective inhibitor in combination with pembrolizumab (P) in WT metastatic urothelial carcinoma, preliminary analysis. J. Clin. Oncol. 37, 4511 (2019).

    Google Scholar 

  79. Harding, T. C., Long, L., Palencia, S., Zhang, H., Sadra, A., Hestir, K. et al. Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of cancer. Sci. Transl. Med. 5, 178ra39 (2013).

    PubMed  Google Scholar 

  80. Tolcher, A. W., Papadopoulos, K. P., Patnaik, A., Wilson, K., Thayer, S., Zanghi, J. et al. A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors. Ann. Oncol. 27, 526–532 (2016).

    CAS  PubMed  Google Scholar 

  81. Morgensztern, D., Karaseva, N., Felip, E., Delgado, I., Burdaeva, O., Domine, M. et al. An open-label phase IB study to evaluate GSK3052230 in combination with paclitaxel and carboplatin, or docetaxel, in FGFR1-amplified non-small cell lung cancer. Lung Cancer 136, 74–79 (2019).

    PubMed  Google Scholar 

  82. van Brummelen, E. M. J., Levchenko, E., Domine, M., Fennell, D. A., Kindler, H. L., Viteri, S. et al. A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma. Investig. New Drugs 38, 457–467 (2020).

    CAS  Google Scholar 

  83. Pal, S. K., Rosenberg, J. E., Hoffman-Censits, J. H., Berger, R., Quinn, D. I., Galsky, M. D. et al. Efficacy of BGJ398, a fibroblast growth factor receptor 1–3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. Cancer Discov. 8, 812–821 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Necchi, A., Pouessel, D., Leibowitz-Amit, R., Flechon, A., Gupta, S., Barthelemy, P. et al. Interim results of fight-201, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with metastatic or surgically unresectable urothelial carcinoma (UC) harboring fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations (GA). Ann. Oncol. 29(suppl 8), VIII319–VIII320 (2018).

    Google Scholar 

  85. Schuler, M., Cho, B. C., Sayehli, C. M., Navarro, A., Soo, R. A., Richly, H. et al. Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 20, 1454–1466 (2019).

    CAS  PubMed  Google Scholar 

  86. Javle, M., Kelley, R. K., Roychowdhury, S., Weiss, K. H., Abou-Alfa, G. K., Macarulla, T. et al. Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions. Ann. Oncol. 29(suppl 8), VIII720 (2018).

    Google Scholar 

  87. Vogel, A. (ed.). FIGHT-202: a phase II study of pemigatinib in patients with previously treated locally advanced or metastatic cholangiocarcinoma. ESMO 2019 Congress; 2019; Barcelona, Spain. Ann. Oncol. 30(Suppl_5), v851–v934 (2019).

  88. Bahleda, R., Italiano, A., Hierro, C., Mita, A., Cervantes, A., Chan, N. et al. Multicenter phase I study of erdafitinib (JNJ-42756493), oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced or refractory solid tumors. Clin. Cancer Res. 25, 4888–4897 (2019).

    CAS  PubMed  Google Scholar 

  89. Park, J. O., Feng, Y.-H., Chen, Y.-Y., Su, W.-C., Oh, D.-Y., Shen, L. et al. Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations. J. Clin. Oncol. 37, 4117 (2019).

    Google Scholar 

  90. Goyal, L., Shi, L., Liu, L. Y., Fece de la Cruz, F., Lennerz, J. K., Raghavan, S. et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov. 9, 1064–1079 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Meric-Bernstam, F., Arkenau, H., Tran, B., Bahleda, R., Kelley, R., Hierro, C. et al. Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors. Ann. Oncol. 29(Suppl_5), O–001 (2018).

    Google Scholar 

  92. Tao, J. J., Schram, A. M. & Hyman, D. M. Basket studies: redefining clinical trials in the era of genome-driven oncology. Annu. Rev. Med. 69, 319–331 (2018).

    CAS  PubMed  Google Scholar 

  93. Yanochko, G. M., Vitsky, A., Heyen, J. R., Hirakawa, B., Lam, J. L., May, J. et al. Pan-FGFR inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and cardiovascular dysfunction. Toxicol. Sci. 135, 451–464 (2013).

    CAS  PubMed  Google Scholar 

  94. Betrian, S., Gomez-Roca, C., Vigarios, E., Delord, J. P. & Sibaud, V. Severe onycholysis and eyelash trichomegaly following use of new selective pan-FGFR inhibitors. JAMA Dermatol. 153, 723–725 (2017).

    PubMed  Google Scholar 

  95. Carr, D. R., Pootrakul, L., Chen, H. Z. & Chung, C. G. Metastatic calcinosis cutis associated with a selective FGFR inhibitor. JAMA Dermatol. 155, 122–123 (2019).

    PubMed  Google Scholar 

  96. Kim, R. D., Sarker, D., Meyer, T., Yau, T., Macarulla, T., Park, J. W. et al. First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 9, 1696–1707 (2019).

    CAS  PubMed  Google Scholar 

  97. Goyal, L., Saha, S. K., Liu, L. Y., Siravegna, G., Leshchiner, I., Ahronian, L. G. et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov. 7, 252–263 (2017).

    CAS  PubMed  Google Scholar 

  98. Krook, M. A., Lenyo, A., Wilberding, M., Barker, H., Dantuono, M., Bailey, K. M. et al. Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma. Mol. Cancer Ther. 19, 847–857 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Krook, M. A., Bonneville, R., Chen, H. Z., Reeser, J. W., Wing, M. R., Martin, D. M. et al. Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy. Cold Spring Harb. Mol. Case Stud. 5, a004002 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Patani, H., Bunney, T. D., Thiyagarajan, N., Norman, R. A., Ogg, D., Breed, J. et al. Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use. Oncotarget 7, 24252–24268 (2016).

    PubMed  PubMed Central  Google Scholar 

  101. Byron, S. A., Chen, H., Wortmann, A., Loch, D., Gartside, M. G., Dehkhoda, F. et al. The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors. Neoplasia 15, 975–988 (2013).

    PubMed  PubMed Central  Google Scholar 

  102. Hahn, N. M., Bivalacqua, T. J., Ross, A. E., Netto, G. J., Baras, A., Park, J. C. et al. A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression: Hoosier Cancer Research Network Trial HCRN 12-157. Clin. Cancer Res. 23, 3003–3011 (2017).

    CAS  PubMed  Google Scholar 

  103. Malchers, F., Ercanoglu, M., Schutte, D., Castiglione, R., Tischler, V., Michels, S. et al. Mechanisms of primary drug resistance in FGFR1-amplified lung cancer. Clin. Cancer Res. 23, 5527–5536 (2017).

    CAS  PubMed  Google Scholar 

  104. Chen, J., Bell, J., Lau, B. T., Whittaker, T., Stapleton, D. & Ji, H. P. A functional CRISPR/Cas9 screen identifies kinases that modulate FGFR inhibitor response in gastric cancer. Oncogenesis 8, 33 (2019).

    PubMed  PubMed Central  Google Scholar 

  105. Cowell, J. K., Qin, H., Hu, T., Wu, Q., Bhole, A. & Ren, M. Mutation in the FGFR1 tyrosine kinase domain or inactivation of PTEN is associated with acquired resistance to FGFR inhibitors in FGFR1-driven leukemia/lymphomas. Int. J. Cancer 141, 1822–1829 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Chang, J., Wang, S., Zhang, Z., Liu, X., Wu, Z., Geng, R. et al. Multiple receptor tyrosine kinase activation attenuates therapeutic efficacy of the fibroblast growth factor receptor 2 inhibitor AZD4547 in FGFR2 amplified gastric cancer. Oncotarget 6, 2009–2022 (2015).

    PubMed  Google Scholar 

  107. Hanker, A. B., Garrett, J. T., Estrada, M. V., Moore, P. D., Ericsson, P. G., Koch, J. P. et al. HER2-overexpressing breast cancers amplify FGFR signaling upon acquisition of resistance to dual therapeutic blockade of HER2. Clin. Cancer Res. 23, 4323–4334 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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