Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Fibroblast growth factor receptors as treatment targets in clinical oncology

Nature Reviews Clinical Oncology volume 16, pages 105–122 (2019)Cite this article

Subjects

Abstract

FGFRs are receptor tyrosine kinases with a role in several biological processes, such as the regulation of development and tissue repair. However, alterations in FGFRs 1–4, such as amplifications, fusions and mutations, as well as aberrant epigenetic or transcriptional regulation and changes in tumour–stromal interactions in the tumour microenvironment, can lead to the development and/or progression of cancer. Similar to other kinase alterations, such alterations are targetable using small molecules or antibodies, and the benefits of FGFR inhibitors have been demonstrated in clinical trials involving subsets of patients with solid tumours harbouring FGFR alterations. However, the response rates in patients with FGFR alterations were relatively low, and responses in patients without detectable FGFR alterations were also observed. In this Review, the author describes the clinical experience with FGFR inhibitors to date, and highlights key aspects that might lead to improved response rates and/or the avoidance of acquired resistance, including the selection of patients who are most likely to benefit from treatment, and the use of FGFR inhibitors in combination regimens with other agents.

Key points

  • FGFR1-amplified oestrogen receptor-positive breast cancer and lung squamous cell carcinoma, FGFR2-amplified gastric cancer, FGFR2-fusion-positive intrahepatic cholangiocarcinoma, FGFR2-mutant endometrial uterine cancer and FGFR3-mutant urothelial carcinoma can all be treated using FGFR inhibitors.

  • Small-molecule inhibitors are the main therapeutic modality used to target FGFR signalling; these agents are classified as either FGFR1/2/3 inhibitors, FGFR4 inhibitors, pan-FGFR inhibitors and multikinase FGFR inhibitors.

  • Antibody-based agents, FGF traps and RNA/DNA aptamers are also under investigation as FGFR-targeted therapeutics.

  • Clinical trials have demonstrated the benefits of FGFR inhibitors in subsets of patients, but also low response rates and the emergence of acquired resistance owing to activation of bypass signalling, gatekeeper mutations and intratumour heterogeneity.

  • Positive and negative selection of patients with tumours harbouring FGFR alterations, the exploration of unknown mechanisms of FGFR overexpression in the absence of FGFR alterations and refined combination strategies are all necessary for the successful clinical application of FGFR inhibitors.

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

Access options

Buy this article

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

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

Fig. 1: Landscape of oncogenic FGFR alterations in human cancers.
Fig. 2: Distribution of common FGFR-mutant cancers.
Fig. 3: Alignment of the tyrosine kinase domains of FGFRs, RET, VEGFRs, CSF1R, FLT3, KIT and PDGFRs.
Fig. 4: Mechanisms of resistance to FGFR inhibitors.

Similar content being viewed by others

References

  1. Hirsch, F. R. et al. Lung cancer: current therapies and new targeted treatments. Lancet 389, 299–311 (2017).

    CAS  PubMed  Google Scholar 

  2. Harbeck, N. & Gnant, M. Breast cancer. Lancet 389, 1134–1150 (2017).

    PubMed  Google Scholar 

  3. Rosti, G., Castagnetti, F., Gugliotta, G. & Baccarani, M. Tyrosine kinase inhibitors in chronic myeloid leukaemia: which, when, for whom? Nat. Rev. Clin. Oncol. 14, 141–154 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Ramalingam, S. S. et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J. Clin. Oncol. 36, 841–849 (2018).

    CAS  PubMed  Google Scholar 

  6. Loibl, S. & Gianni, L. HER2-positive breast cancer. Lancet 389, 2415–2429 (2017).

    CAS  PubMed  Google Scholar 

  7. Wu, F., Zhang, Y., Sun, B., McMahon, A. P. & Wang, Y. Hedgehog signaling: from basic biology to cancer therapy. Cell Chem. Biol. 24, 252–280 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Tannock, I. F. & Hickman, J. A. Limits to personalized cancer medicine. N. Engl. J. Med. 375, 1289–1294 (2016).

    PubMed  Google Scholar 

  9. Massard, C. et al. High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial. Cancer Discov. 7, 586–595 (2017).

    CAS  PubMed  Google Scholar 

  10. Drilon, A., Hu, Z. I., Lai, G. G. Y. & Tan, D. S. W. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat. Rev. Clin. Oncol. 15, 151–167 (2018).

    CAS  PubMed  Google Scholar 

  11. Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Katoh, M. & Nakagama, H. FGF receptors: cancer biology and therapeutics. Med. Res. Rev. 34, 280–300 (2014).

    CAS  PubMed  Google Scholar 

  13. 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 

  14. Chen, H. et al. Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases. eLife 6, e21137 (2017).

    PubMed  PubMed Central  Google Scholar 

  15. Helsten, T. et al. 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 

  16. Tanner, Y. & Grose, R. P. Dysregulated FGF signalling in neoplastic disorders. Semin. Cell Dev. Biol. 53, 126–135 (2016).

    CAS  PubMed  Google Scholar 

  17. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. 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 

  22. Jin, L., Nonaka, Y., Miyakawa, S., Fujiwara, M. & Nakamura, Y. Dual therapeutic action of a neutralizing anti-FGF2 aptamer in bone disease and bone cancer Pain. Mol. Ther. 24, 1974–1986 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Moore, R. et al. Sequence, topography and protein coding potential of mouse int-2: a putative oncogene activated by mouse mammary tumour virus. EMBO J. 5, 919–924 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Katoh, M. WNT and FGF gene clusters. Int. J. Oncol. 21, 1269–1273 (2002).

    CAS  PubMed  Google Scholar 

  25. Liu, H. et al. Identifying and targeting sporadic oncogenic genetic aberrations in mouse models of triple-negative breast cancer. Cancer Discov. 8, 354–369 (2018).

    CAS  PubMed  Google Scholar 

  26. Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Turner, N. et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene 29, 2013–2023 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. André, F. et al. Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin. Cancer Res. 15, 441–451 (2009).

    PubMed  Google Scholar 

  29. Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47–54 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Chung, J. H. et al. Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer. Ann. Oncol. 28, 2866–2873 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Khoo, B. L. et al. Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy. Oncotarget 6, 15578–15593 (2015).

    PubMed  PubMed Central  Google Scholar 

  32. Brunello, E. et al. FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma. J. Exp. Clin. Cancer Res. 31, 103 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, W. et al. A versatile tumor gene deletion system reveals a crucial role for FGFR1 in breast cancer metastasis. Neoplasia 19, 421–428 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Luo, J. et al. An mRNA gene expression-based signature to identify FGFR1-amplified estrogen receptor-positive breast tumors. J. Mol. Diagn. 19, 147–161 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wu, Y. M. et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 3, 636–647 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Reintjes, N. et al. Activating somatic FGFR2 mutations in breast cancer. PLOS ONE 8, e60264 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Yu, M. et al. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 345, 216–220 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Turczyk, L. et al. FGFR2-driven signaling counteracts tamoxifen effect on ERα-positive breast cancer cells. Neoplasia 19, 791–804 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Campbell, T. M., Castro, M. A. A., de Oliveira, K. G., Ponder, B. A. J. & Meyer, K. B. ERα binding by transcription factors NFIB and YBX1 enables FGFR2 signaling to modulate estrogen responsiveness in breast cancer. Cancer Res. 78, 410–421 (2018).

    CAS  PubMed  Google Scholar 

  40. Huang, Y. L. et al. FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis. Hum. Mol. Genet. 24, 3506–3517 (2015).

    CAS  PubMed  Google Scholar 

  41. André, F. et al. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin. Cancer Res. 19, 3693–3702 (2013).

    PubMed  Google Scholar 

  42. Weiss, J. et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci. Transl Med. 2, 62ra93 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Peifer, M. et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat. Genet. 44, 1104–1110 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Pros, E. et al. Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer. Int. J. Cancer 133, 898–907 (2013).

    CAS  PubMed  Google Scholar 

  45. Campbell, J. D. et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet. 48, 607–616 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Hirsch, F. R., Suda, K., Wiens, J. & Bunn, P. A. Jr. New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet 388, 1012–1024 (2016).

    PubMed  Google Scholar 

  47. Chandrani, P. et al. Drug-sensitive FGFR3 mutations in lung adenocarcinoma. Ann. Oncol. 28, 597–603 (2017).

    CAS  PubMed  Google Scholar 

  48. Kim, Y. et al. Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients. J. Clin. Oncol. 32, 121–128 (2014).

    CAS  PubMed  Google Scholar 

  49. Tchaicha, J. H. et al. Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a pan-FGFR inhibitor in a mouse model of NSCLC. Cancer Res. 74, 4676–4684 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Seo, J. S. et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res. 22, 2109–2119 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Cihoric, N. et al. Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer. Br. J. Cancer 110, 2914–2922 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Preusser, M. et al. High rate of FGFR1 amplifications in brain metastases of squamous and non-squamous lung cancer. Lung Cancer 83, 83–89 (2014).

    PubMed  Google Scholar 

  53. Carter, L. et al. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat. Med. 23, 114–119 (2017).

    CAS  PubMed  Google Scholar 

  54. Polley, E. et al. Small cell lung cancer screen of oncology drugs, investigational agents, and gene and microRNA expression. J. Natl. Cancer Inst. 108, dwj122 (2016).

    Google Scholar 

  55. Ross, J. S. et al. Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod. Pathol. 27, 271–280 (2014).

    CAS  PubMed  Google Scholar 

  56. Kawamata, F. et al. Copy number profiles of paired primary and metastatic colorectal cancers. Oncotarget 9, 3394–3405 (2017).

    PubMed  PubMed Central  Google Scholar 

  57. Kim, H. S. et al. Fibroblast growth factor receptor 1 gene amplification is associated with poor survival in patients with resected esophageal squamous cell carcinoma. Oncotarget 6, 2562–2572 (2015).

    PubMed  Google Scholar 

  58. Schäfer, M. H. et al. Fibroblast growth factor receptor 1 gene amplification in gastric adenocarcinoma. Hum. Pathol. 46, 1488–1495 (2015).

    PubMed  Google Scholar 

  59. Clauditz, T. S. et al. Prevalence of fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell carcinomas of the head and neck. J. Cancer Res. Clin. Oncol. 144, 53–61 (2018).

    CAS  PubMed  Google Scholar 

  60. Gorringe, K. L. et al. High-resolution single nucleotide polymorphism array analysis of epithelial ovarian cancer reveals numerous microdeletions and amplifications. Clin. Cancer Res. 13, 4731–4739 (2007).

    CAS  PubMed  Google Scholar 

  61. Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Edwards, J., Krishna, N. S., Witton, C. J. & Bartlett, J. M. Gene amplifications associated with the development of hormone-resistant prostate cancer. Clin. Cancer Res. 9, 5271–5281 (2003).

    CAS  PubMed  Google Scholar 

  63. Chiosea, S. I. et al. Molecular characterization of apocrine salivary duct carcinoma. Am. J. Surg. Pathol. 39, 744–752 (2015).

    PubMed  Google Scholar 

  64. Heitzer, E. et al. Expanded molecular profiling of myxofibrosarcoma reveals potentially actionable targets. Mod. Pathol. 30, 1698–1709 (2017).

    CAS  PubMed  Google Scholar 

  65. Amary, M. F. et al. Fibroblastic growth factor receptor 1 amplification in osteosarcoma is associated with poor response to neo-adjuvant chemotherapy. Cancer Med. 3, 980–987 (2014).

    Google Scholar 

  66. Missiaglia, E. et al. Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: an approach to identify candidate genes involved in tumor development. Genes Chromosomes Cancer 48, 455–467 (2009).

    CAS  PubMed  Google Scholar 

  67. Chudasama, P. et al. Targeting fibroblast growth factor receptor 1 for treatment of soft-tissue sarcoma. Clin. Cancer Res. 23, 962–973 (2017).

    CAS  PubMed  Google Scholar 

  68. Holbrook, J. D. et al. Deep sequencing of gastric carcinoma reveals somatic mutations relevant to personalized medicine. J. Transl Med. 9, 119 (2011).

    PubMed  PubMed Central  Google Scholar 

  69. Deng, N. et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61, 673–684 (2012).

    CAS  PubMed  Google Scholar 

  70. Wadhwa, R. et al. Gastric cancer — molecular and clinical dimensions. Nat. Rev. Clin. Oncol. 10, 643–655 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Jung, E. J., Jung, E. J., Min, S. Y., Kim, M. A. & Kim, W. H. Fibroblast growth factor receptor 2, gene amplification status and its clinicopathologic significance in gastric carcinoma. Hum. Pathol. 43, 1559–1566 (2012).

    CAS  PubMed  Google Scholar 

  72. Su, X. et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br. J. Cancer 110, 967–975 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Ajani, J. A. et al. Gastric adenocarcinoma. Nat. Rev. Dis. Primers 3, 17036 (2017).

    PubMed  Google Scholar 

  74. Murase, H. et al. Prognostic significance of the co-overexpression of fibroblast growth factor receptors 1, 2 and 4 in gastric cancer. Mol. Clin. Oncol. 2, 509–517 (2014).

    PubMed  PubMed Central  Google Scholar 

  75. Ahn, S. et al. FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival. Mod. Pathol. 29, 1095–1103 (2016).

    CAS  PubMed  Google Scholar 

  76. Kim, S. Y. et al. Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion. Oncotarget 8, 15014–15022 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. Jang, J. et al. Antitumor effect of AZD4547 in a fibroblast growth factor receptor 2-amplified gastric cancer patient-derived cell model. Transl Oncol. 10, 469–475 (2017).

    PubMed  PubMed Central  Google Scholar 

  78. Greer, S. U. et al. Linked read sequencing resolves complex genomic rearrangements in gastric cancer metastases. Genome Med. 9, 57 (2017).

    PubMed  PubMed Central  Google Scholar 

  79. Pearson, A. et al. High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial. Cancer Discov. 6, 838–851 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Guagnano, V. et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov. 2, 1118–1133 (2012).

    CAS  PubMed  Google Scholar 

  81. Xie, L. et al. FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin. Cancer Res. 19, 2572–2583 (2013).

    CAS  PubMed  Google Scholar 

  82. Zhang, T. et al. Patient-derived gastric carcinoma xenograft mouse models faithfully represent human tumor molecular diversity. PLOS ONE 10, e0134493 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Lau, W. M. et al. Acquired resistance to FGFR inhibitor in diffuse-type gastric cancer through an AKT-independent PKC-mediated phosphorylation of GSK3β. Mol. Cancer Ther. 17, 232–242 (2018).

    CAS  PubMed  Google Scholar 

  85. Glaser, A. P., Fantini, D., Shilatifard, A., Schaeffer, E. M. & Meeks, J. J. The evolving genomic landscape of urothelial carcinoma. Nat. Rev. Urol. 14, 215–229 (2017).

    CAS  PubMed  Google Scholar 

  86. Sanli, O. et al. Bladder cancer. Nat. Rev. Dis. Primers 3, 17022 (2017).

    PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  88. Pietzak, E. J. et al. Next-generation sequencing of nonmuscle invasive bladder cancer reveals potential biomarkers and rational therapeutic targets. Eur. Urol. 72, 952–959 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Gao, Q. et al. Driver fusions and their implications in the development and treatment of human cancers. Cell Rep. 23, 227–238 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. van Kessel, K. E. M. et al. Molecular markers increase precision of the European Association of Urology non-muscle-invasive bladder cancer progression risk groups. Clin. Cancer Res. 24, 1586–1593 (2018).

    PubMed  Google Scholar 

  91. Singh, D. et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337, 1231–1235 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Parker, B. C. et al. The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma. J. Clin. Invest. 123, 855–865 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Nelson, K. N. et al. Oncogenic gene fusion FGFR3-TACC3 is regulated by tyrosine phosphorylation. Mol. Cancer Res. 14, 458–469 (2016).

    CAS  PubMed  Google Scholar 

  94. Frattini, V. et al. A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature 553, 222–227 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Sarkar, S., Ryan, E. L. & Royle, S. J. FGFR3-TACC3 cancer gene fusions cause mitotic defects by removal of endogenous TACC3 from the mitotic spindle. Open Biol. 7, 170080 (2017).

    PubMed  PubMed Central  Google Scholar 

  96. Schram, A. M., Chang, M. T., Jonsson, P. & Drilon, A. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat. Rev. Clin. Oncol. 14, 735–748 (2017).

    CAS  PubMed  Google Scholar 

  97. Byron, S. A. et al. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features. PLOS ONE 7, e30801 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013).

    Google Scholar 

  99. Jeske, Y. W. et al. FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol. Oncol. 145, 366–373 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Spaans, V. M. et al. Designing a high-throughput somatic mutation profiling panel specifically for gynaecological cancers. PLOS ONE 9, e93451 (2014).

    PubMed  PubMed Central  Google Scholar 

  101. Weberpals, J. I. et al. Vulvar squamous cell carcinoma (VSCC) as two diseases: HPV status identifies distinct mutational profiles including oncogenic fibroblast growth factor receptor 3. Clin. Cancer Res. 23, 4501–4510 (2017).

    CAS  PubMed  Google Scholar 

  102. Kumar, K. R., Chen, W., Koduru, P. R. & Luu, H. S. Myeloid and lymphoid neoplasm with abnormalities of FGFR1 presenting with trilineage blasts and RUNX1 rearrangement: a case report and review of literature. Am. J. Clin. Pathol. 143, 738–748 (2015).

    CAS  PubMed  Google Scholar 

  103. Yagasaki, F. et al. Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T cell lymphoma with a t(4;12)(p16; p13) chromosomal translocation. Cancer Res. 61, 8371–8374 (2001).

    CAS  PubMed  Google Scholar 

  104. Cowell, J. K., Qin, H., Chang, C. S., Kitamura, E. & Ren, M. A model of BCR-FGFR1 driven human AML in immunocompromised mice. Br. J. Haematol. 175, 542–545 (2016).

    CAS  PubMed  Google Scholar 

  105. Chesi, M. et al. Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 97, 729–736 (2001).

    CAS  PubMed  Google Scholar 

  106. Reifenberger, G., Wirsching, H. G., Knobbe-Thomsen, C. B. & Weller, M. Advances in the molecular genetics of gliomas — implications for classification and therapy. Nat. Rev. Clin. Oncol. 14, 434–452 (2017).

    CAS  PubMed  Google Scholar 

  107. Blumenthal, D. T. et al. Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients. J. Neurooncol. 130, 211–219 (2016).

    CAS  PubMed  Google Scholar 

  108. Granberg, K. J. et al. Strong FGFR3 staining is a marker for FGFR3 fusions in diffuse gliomas. Neuro. Oncol. 19, 1206–1216 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhang, J. et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat. Genet. 45, 602–612 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Qaddoumi, I. et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol. 131, 833–845 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Jones, D. T. et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat. Genet. 45, 927–932 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Huse, J. T. et al. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol. 133, 417–429 (2017).

    CAS  PubMed  Google Scholar 

  113. Lazo de la Vega, L. et al. Comprehensive molecular profiling of olfactory neuroblastoma identifies potentially targetable FGFR3 amplifications. Mol. Cancer Res. 15, 1551–1557 (2017).

    CAS  PubMed  Google Scholar 

  114. Sia, D., Villanueva, A., Friedman, S. L. & Llovet, J. M. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152, 745–761 (2017).

    CAS  PubMed  Google Scholar 

  115. Ahn, S. M. et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 60, 1972–1982 (2014).

    CAS  PubMed  Google Scholar 

  116. Ross, J. S. et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 19, 235–242 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Sia, D. et al. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat. Commun. 6, 6087 (2015).

    CAS  PubMed  Google Scholar 

  118. Valle, J. W., Lamarca, A., Goyal, L., Barriuso, J. & Zhu, A. X. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 7, 943–962 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Agelopoulos, K. et al. Deep sequencing in conjunction with expression and functional analyses reveals activation of FGFR1 in Ewing sarcoma. Clin. Cancer Res. 21, 4935–4946 (2015).

    CAS  PubMed  Google Scholar 

  120. Nannini, M., Urbini, M., Astolfi, A., Biasco, G. & Pantaleo, M. A. The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST). J. Transl Med. 15, 113 (2017).

    PubMed  PubMed Central  Google Scholar 

  121. Toledo, R. A. et al. Recurrent mutations of chromatin-remodeling genes and kinase receptors in pheochromocytomas and paragangliomas. Clin. Cancer Res. 22, 2301–2310 (2016).

    CAS  PubMed  Google Scholar 

  122. Shi, E. et al. FGFR1 and NTRK3 actionable alterations in “wild-type” gastrointestinal stromal tumors. J. Transl Med. 14, 339 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. Lee, J. C. et al. Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Mod. Pathol. 29, 1335–1346 (2016).

    CAS  PubMed  Google Scholar 

  124. Haugh, A. M. et al. Distinct patterns of acral melanoma based on site and relative sun exposure. J. Invest. Dermatol. 138, 384–393 (2018).

    CAS  PubMed  Google Scholar 

  125. Li, C. et al. Oncogene mutation profiling reveals poor prognosis associated with FGFR1/3 mutation in liposarcoma. Hum. Pathol. 55, 143–150 (2016).

    PubMed  Google Scholar 

  126. Taylor, J. G. 6th et al. Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J. Clin. Invest. 119, 3395–3407 (2009).

    CAS  PubMed  Google Scholar 

  127. Cheng, W., Wang, M., Tian, X. & Zhang, X. An overview of the binding models of FGFR tyrosine kinases in complex with small molecule inhibitors. Eur. J. Med. Chem. 126, 476–490 (2017).

    CAS  PubMed  Google Scholar 

  128. Knoepfel, T. et al. 2-formylpyridyl ureas as highly selective reversible-covalent inhibitors of fibroblast growth factor receptor 4. ACS Med. Chem. Lett. 9, 215–220 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Mo, C. et al. 2-aminopyrimidine derivatives as new selective fibroblast growth factor receptor 4 (FGFR4) inhibitors. ACS Med. Chem. Lett. 8, 543–548 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Cui, J. et al. Optimization of 1H-indazol-3-amine derivatives as potent fibroblast growth factor receptor inhibitors. Bioorg. Med. Chem. Lett. 27, 3782–3786 (2017).

    CAS  PubMed  Google Scholar 

  131. Li, X. et al. 2-oxo-3, 4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives as new irreversible pan fibroblast growth factor receptor (FGFR) inhibitors. Eur. J. Med. Chem. 135, 531–543 (2017).

    CAS  PubMed  Google Scholar 

  132. Wei, M. et al. Design, synthesis and biological evaluation of a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent fibroblast growth factor receptor (FGFR) inhibitors. Eur. J. Med. Chem. 154, 9–28 (2018).

    CAS  PubMed  Google Scholar 

  133. Zhu, W. et al. Design, synthesis, and pharmacological evaluation of novel multisubstituted pyridin-3-amine derivatives as multitargeted protein kinase inhibitors for the treatment of non-small cell lung cancer. J. Med. Chem. 60, 6018–6035 (2017).

    CAS  PubMed  Google Scholar 

  134. Zhang, Y. et al. Discovery and biological evaluation of a series of pyrrolo[2,3-b]pyrazines as novel FGFR inhibitors. Molecules 22, E583 (2017).

    PubMed  Google Scholar 

  135. Roskoski, R. Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol. Res. 103, 26–48 (2016).

    CAS  PubMed  Google Scholar 

  136. Bhullar, K. S. et al. Kinase-targeted cancer therapies: progress, challenges and future directions. Mol. Cancer 17, 48 (2018).

    PubMed  PubMed Central  Google Scholar 

  137. Gavine, P. R. et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 72, 2045–2056 (2012).

    CAS  PubMed  Google Scholar 

  138. Tucker, J. A. et al. Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4. Structure 22, 1764–1774 (2014).

    CAS  PubMed  Google Scholar 

  139. O’Hare, T. et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16, 401–412 (2009).

    PubMed  PubMed Central  Google Scholar 

  140. Miyano, S. M. et al. E7090, a novel selective inhibitor of fibroblast growth factor receptors, displays potent antitumor activity and prolongs survival in preclinical models. Mol. Cancer Ther. 15, 2630–2639 (2016).

    CAS  Google Scholar 

  141. Tohyama, O. et al. Antitumor activity of lenvatinib (E7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J. Thyroid Res. 2014, 638747 (2014).

    PubMed  PubMed Central  Google Scholar 

  142. Okamoto, K. et al. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med. Chem. Lett. 6, 89–94 (2014).

    PubMed  PubMed Central  Google Scholar 

  143. Hagel, M. et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov. 5, 424–437 (2015).

    CAS  PubMed  Google Scholar 

  144. Tan, L. et al. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. Proc. Natl Acad. Sci. USA 111, E4869–E4877 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Joshi, J. J. et al. H3B-6527 is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer Res. 77, 6999–7013 (2017).

    CAS  PubMed  Google Scholar 

  146. Venetsanakos, E. et al. The irreversible covalent fibroblast growth factor receptor inhibitor PRN1371 exhibits sustained inhibition of FGFR after drug clearance. Mol. Cancer Ther. 16, 2668–2676 (2017).

    CAS  PubMed  Google Scholar 

  147. Nakanishi, Y. et al. The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol. Cancer Ther. 13, 2547–2558 (2014).

    CAS  PubMed  Google Scholar 

  148. Jurek, P. M. et al. Anti-FGFR1 aptamer-tagged superparamagnetic conjugates for anticancer hyperthermia therapy. Int. J. Nanomed. 12, 2941–2950 (2017).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  150. Tolcher, A. W. 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 

  151. Liu, Z. et al. Binding of human recombinant mutant soluble ectodomain of FGFR2IIIc to c subtype of FGFRs: implications for anticancer activity. Oncotarget 7, 68473–68488 (2016).

    PubMed  PubMed Central  Google Scholar 

  152. Garcia, S. et al. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci. Transl Med. 5, 203ra124 (2013).

    PubMed  Google Scholar 

  153. de Aguiar, R. B. et al. Blocking FGF2 with a new specific monoclonal antibody impairs angiogenesis and experimental metastatic melanoma, suggesting a potential role in adjuvant settings. Cancer Lett. 371, 151–160 (2016).

    PubMed  Google Scholar 

  154. Wang, S. et al. Construction of a human monoclonal antibody against bFGF for suppression of NSCLC. J. Cancer 9, 2003–2011 (2018).

    PubMed  PubMed Central  Google Scholar 

  155. Urano, A. & Kamai, Y. Combination of anti-FGFR2 antibody and other agents. WO2015053407A1 (2014).

  156. Bai, A. 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 

  157. Bendell, J. C. et al. FPA144-001: a first in human study of FPA 144, an ADCC-enhanced, FGFR2b isoform-selective monoclonal antibody in patients with advanced solid tumors. J. Clin. Oncol. 34, (Suppl. 4), 140 (2016).

    Google Scholar 

  158. Bellmunt, J. et al. Safety and efficacy of docetaxel plus b-701, a selective inhibitor of FGFR3, in subjects with advanced or metastatic urothelial carcinoma. J. Clin. Oncol. 35 (Suppl. 15), 4540 (2017).

    Google Scholar 

  159. O’Donnell, P. 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 (Suppl. 6), 191–192 (2012).

    Google Scholar 

  160. Bartz, R. et al. U3-1784, a human anti-FGFR4 antibody for the treatment of cancer. Cancer Res. 76 (Suppl. 14), 3852 (2016).

    Google Scholar 

  161. Sokolowska-Wedzina, A. et al. High-affinity internalizing human scFv-Fc antibody for targeting FGFR1-overexpressing lung cancer. Mol. Cancer Res. 15, 1040–1050 (2017).

    CAS  PubMed  Google Scholar 

  162. Sommer, A. 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 

  163. Borek, A., Sokolowska-Wedzina, A., Chodaczek, G. & Otlewski, J. Generation of high-affinity, internalizing anti-FGFR2 single-chain variable antibody fragment fused with Fc for targeting gastrointestinal cancers. PLOS ONE 13, e0192194 (2018).

    PubMed  PubMed Central  Google Scholar 

  164. 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 

  165. Bono, F. et al. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer Cell 23, 477–488 (2013).

    CAS  PubMed  Google Scholar 

  166. Tsimafeyeu, I. et al. Molecular modeling, de novo design and synthesis of a novel, extracellular binding fibroblast growth factor receptor 2 inhibitor alofanib (RPT835). Med. Chem. 12, 303–317 (2016).

    CAS  PubMed  Google Scholar 

  167. Li, Q. et al. Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression. J. Biol. Chem. 293, 6434–6448 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Paik, P. K. et al. A phase Ib open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers. Clin. Cancer Res. 23, 5366–5373 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Van Cutsem, E. et al. A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification. Ann. Oncol. 28, 1316–1324 (2017).

    PubMed  Google Scholar 

  170. Papadopoulos, K. P. et al. A phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br. J. Cancer 117, 1592–1599 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Das, M. et al. Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: a drug-drug interaction. Lung Cancer 89, 280–286 (2015).

    PubMed  Google Scholar 

  172. Milowsky, M. I. et al. Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma. Eur. J. Cancer 50, 3145–3152 (2014).

    CAS  PubMed  Google Scholar 

  173. Konecny, G. E. et al. Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study. Lancet Oncol. 16, 686–694 (2015).

    CAS  PubMed  Google Scholar 

  174. Scheid, C. et al. Phase 2 study of dovitinib in patients with relapsed or refractory multiple myeloma with or without t(4;14) translocation. Eur. J. Haematol. 95, 316–324 (2015).

    CAS  PubMed  Google Scholar 

  175. Lim, S. H. et al. Efficacy and safety of dovitinib in pretreated patients with advanced squamous non-small cell lung cancer with FGFR1 amplification: a single-arm, phase 2 study. Cancer 122, 3024–3031 (2016).

    CAS  PubMed  Google Scholar 

  176. Musolino, A. et al. Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR+, HER2− breast cancer that had progressed during or after prior endocrine therapy. Breast Cancer Res. 19, 18 (2017).

    PubMed  PubMed Central  Google Scholar 

  177. Hahn, N. M. 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 

  178. Slosberg, E. D. et al. Signature program: a platform of basket trials. Oncotarget 9, 21383–21395 (2018).

    PubMed  PubMed Central  Google Scholar 

  179. Tabernero, J. et al. 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 (2015).

    CAS  PubMed  Google Scholar 

  180. Nishina, T. et al. Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Invest. New Drugs 36, 424–434 (2018).

    CAS  PubMed  Google Scholar 

  181. Nogova, L. et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1–3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J. Clin. Oncol. 35, 157–165 (2017).

    CAS  PubMed  Google Scholar 

  182. Javle, M. et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J. Clin. Oncol. 36, 276–282 (2018).

    CAS  PubMed  Google Scholar 

  183. Soria, J. C. et al. Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors. Ann. Oncol. 25, 2244–2251 (2014).

    PubMed  Google Scholar 

  184. Michael, M. et al. A phase 1 study of LY2874455, an oral selective pan-FGFR inhibitor, in patients with advanced cancer. Target Oncol. 12, 463–474 (2017).

    PubMed  Google Scholar 

  185. Perera, T. P. S. 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 

  186. Wellstein, A., Giaccone, G., Atkins, M. B. & Sausville, E. A. in Goodman & Gilman’s: The Pharmacological Basis of Therapeutics 13th edn (eds Brunton, L. L., Chabner, B. A., Knollmann, B. C.) 1203–1236 (McGraw-Hill Education, New York, 2018).

  187. Hall, T. G. et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLOS ONE 11, e0162594 (2016).

    PubMed  PubMed Central  Google Scholar 

  188. Bello, E. et al. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 71, 1396–1405 (2011).

    CAS  PubMed  Google Scholar 

  189. Hilberg, F. et al. Triple angiokinase inhibitor nintedanib directly inhibits tumor cell growth and induces tumor shrinkage via blocking oncogenic receptor tyrosine kinases. J. Pharmacol. Exp. Ther. 364, 494–503 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Burbridge, M. F. et al. S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab. Mol. Cancer Ther. 12, 1749–1762 (2013).

    CAS  PubMed  Google Scholar 

  191. Lin, B. et al. Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRβ and FGFR1. Gene 654, 77–86 (2018).

    CAS  PubMed  Google Scholar 

  192. Jiang, X. F. et al. SOMCL-085, a novel multi-targeted FGFR inhibitor, displays potent anticancer activity in FGFR-addicted human cancer models. Acta Pharmacol. Sin. 39, 243–250 (2018).

    CAS  PubMed  Google Scholar 

  193. Camidge, D. R., Pao, W. & Sequist, L. V. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat. Rev. Clin. Oncol. 11, 473–481 (2014).

    CAS  PubMed  Google Scholar 

  194. Hata, A. N. et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22, 262–269 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Schmitt, M. W., Loeb, L. A. & Salk, J. J. The influence of subclonal resistance mutations on targeted cancer therapy. Nat. Rev. Clin. Oncol. 13, 335–347 (2016).

    CAS  PubMed  Google Scholar 

  196. Gelsi-Boyer, V. et al. Comprehensive profiling of 8p11-12 amplification in breast cancer. Mol. Cancer Res. 3, 655–667 (2005).

    CAS  PubMed  Google Scholar 

  197. Rooney, C. et al. Characterization of FGFR1 locus in sqNSCLC reveals a broad and heterogeneous amplicon. PLOS ONE 11, e0149628 (2016).

    PubMed  PubMed Central  Google Scholar 

  198. Malchers, F. et al. Mechanisms of primary drug resistance in FGFR1-amplified lung cancer. Clin. Cancer Res. 23, 5527–5536 (2017).

    CAS  PubMed  Google Scholar 

  199. Kim, S. M. et al. Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy. Oncogenesis 5, e241 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).

    Google Scholar 

  201. Silva, A. N. S. et al. Frequent coamplification of receptor tyrosine kinase and downstream signaling genes in Japanese primary gastric cancer and conversion in matched lymph node metastasis. Ann. Surg. 267, 114–121 (2018).

    PubMed  Google Scholar 

  202. Chang, J. 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 

  203. Liu, K., Song, X., Zhu, M. & Ma, H. Overexpression of FGFR2 contributes to inherent resistance to MET inhibitors in MET-amplified patient-derived gastric cancer xenografts. Oncol. Lett. 10, 2003–2008 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Wang, H. et al. Establishment of patient-derived gastric cancer xenografts: a useful tool for preclinical evaluation of targeted therapies involving alterations in HER-2, MET and FGFR2 signaling pathways. BMC Cancer 17, 191 (2017).

    PubMed  PubMed Central  Google Scholar 

  205. Collin, M. P. et al. Discovery of rogaratinib (BAY 1163877): a pan-FGFR Inhibitor. ChemMedChem 13, 437–445 (2018).

    CAS  PubMed  Google Scholar 

  206. Herrera-Abreu, M. T. et al. Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer. Cancer Discov. 3, 1058–1071 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Wang, L. et al. A functional genetic screen identifies the phosphoinositide 3-kinase pathway as a determinant of resistance to fibroblast growth factor receptor inhibitors in FGFR mutant urothelial cell carcinoma. Eur. Urol. 71, 858–862 (2017).

    CAS  PubMed  Google Scholar 

  208. Dedes, K. J., Wetterskog, D., Ashworth, A., Kaye, S. B. & Reis-Filho, J. S. Emerging therapeutic targets in endometrial cancer. Nat. Rev. Clin. Oncol. 8, 261–271 (2011).

    CAS  PubMed  Google Scholar 

  209. Konecny, G. E. et al. Activity of the fibroblast growth factor receptor inhibitors dovitinib (TKI258) and NVP-BGJ398 in human endometrial cancer cells. Mol. Cancer Ther. 12, 632–642 (2013).

    CAS  PubMed  Google Scholar 

  210. Kwak, Y., Cho, H., Hur, W. & Sim, T. Antitumor effects and mechanisms of AZD4547 on FGFR2-deregulated endometrial cancer cells. Mol. Cancer Ther. 14, 2292–2302 (2015).

    CAS  PubMed  Google Scholar 

  211. Packer, L. M. et al. PI3K inhibitors synergize with FGFR inhibitors to enhance antitumor responses in FGFR2 mutant endometrial cancers. Mol. Cancer Ther. 16, 637–648 (2017).

    CAS  PubMed  Google Scholar 

  212. Yu, Y. et al. In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor. Anticancer Drugs 28, 503–513 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Goyal, L. 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 

  214. Cowell, J. K. et al. 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 

  215. Chell, V. et al. Tumour 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 (2013).

    CAS  PubMed  Google Scholar 

  216. Byron, S. A. 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 

  217. Kim, H. et al. Novel fusion transcripts in human gastric cancer revealed by transcriptome analysis. Oncogene 33, 5434–5441 (2014).

    CAS  PubMed  Google Scholar 

  218. Okuda, T. et al. Molecular heterogeneity in the novel fusion gene APIP-FGFR2: diversity of genomic breakpoints in gastric cancer with high-level amplifications at 11p13 and 10q26. Oncol. Lett. 13, 215–221 (2017).

    CAS  PubMed  Google Scholar 

  219. Wang, Y. et al. Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein. Cancer Lett. 380, 163–173 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Rizvi, S., Khan, S. A., Hallemeier, C. L., Kelley, R. K. & Gores, G. J. Cholangiocarcinoma — evolving concepts and therapeutic strategies. Nat. Rev. Clin. Oncol. 15, 95–111 (2018).

    CAS  PubMed  Google Scholar 

  221. Shi, J. Y. et al. Inferring the progression of multifocal liver cancer from spatial and temporal genomic heterogeneity. Oncotarget 7, 2867–2877 (2016).

    PubMed  Google Scholar 

  222. Gao, Q. et al. Cell culture system for analysis of genetic heterogeneity within hepatocellular carcinomas and response to pharmacologic agents. Gastroenterology 152, 232–242 (2017).

    CAS  PubMed  Google Scholar 

  223. Kim, S. T. et al. Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+gastric cancer patients. Ann. Oncol. 29, 1037–1048 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Du, J. et al. Circulating tumor DNA profiling by next generation sequencing reveals heterogeneity of crizotinib resistance mechanisms in a gastric cancer patient with MET amplification. Oncotarget 8, 26281–26287 (2017).

    PubMed  PubMed Central  Google Scholar 

  225. Barata, P. C. et al. Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance. Ann. Oncol. 28, 2458–2463 (2017).

    CAS  PubMed  Google Scholar 

  226. Vandekerkhove, G. et al. Circulating tumor DNA reveals clinically actionable somatic genome of metastatic bladder cancer. Clin. Cancer Res. 23, 6487–6497 (2017).

    CAS  PubMed  Google Scholar 

  227. Plagnol, V. et al. Analytical validation of a next generation sequencing liquid biopsy assay for high sensitivity broad molecular profiling. PLOS ONE 13, e0193802 (2018).

    PubMed  PubMed Central  Google Scholar 

  228. Wynes, M. W. et al. FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. Clin. Cancer Res. 20, 3299–3309 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Yuan, Y. et al. Genomic mutation-driven metastatic breast cancer therapy: a single center experience. Oncotarget 8, 26414–26423 (2017).

    PubMed  PubMed Central  Google Scholar 

  230. Johnson, A. et al. Comprehensive genomic profiling of 282 pediatric low- and high-grade gliomas reveals genomic drivers, tumor mutational burden, and hypermutation signatures. Oncologist 22, 1478–1490 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Katoh, M. The integration of genomics testing and functional proteomics in the era of personalized medicine. Expert Rev. Proteomics 14, 1055–1058 (2017).

    CAS  PubMed  Google Scholar 

  233. Tahara, M. et al. Safety, tolerability, pharmacokinetics, and efficacy of pan-fibroblast growth factor receptor inhibitor rogaratinib in Japanese patients with refractory, locally advanced metastatic solid tumors selected with a novel, mRNA-based patient selection strategy. Mol. Cancer Ther. 17, A099 (2018).

    Google Scholar 

  234. Sousa, V. et al. Amplification of FGFR1 gene and expression of FGFR1 protein is found in different histological types of lung carcinoma. Virchows Arch. 469, 173–182 (2016).

    CAS  PubMed  Google Scholar 

  235. Lu, T. et al. The Hippo/YAP1 pathway interacts with FGFR1 signaling to maintain stemness in lung cancer. Cancer Lett. 423, 36–46 (2018).

    CAS  PubMed  Google Scholar 

  236. Wang, F. et al. Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway. Oncotarget 6, 7899–7917 (2015).

    PubMed  PubMed Central  Google Scholar 

  237. Chauvin, C. et al. High-throughput drug screening identifies pazopanib and clofilium tosylate as promising treatments for malignant rhabdoid tumors. Cell Rep. 21, 1737–1745 (2017).

    CAS  PubMed  Google Scholar 

  238. Li, S. Q. et al. Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534). PLOS ONE 8, e76551 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Gonzalez-Ericsson, P. I. et al. Genenomic landscape of breast cancers with FGFR1 amplification and FGFR1/CCND1 co-amplification revealed by targeted capture next generation sequencing. Cancer Res. 78, (Suppl.), PD4-07 (2018).

    Google Scholar 

  240. Giltnane, J. M. et al. Genomic profiling of ER+breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance. Sci. Transl Med. 9, eaai7993 (2017).

    PubMed  PubMed Central  Google Scholar 

  241. Formisano, L. et al. Association of FGFR1 with ERα maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+breast cancer. Clin. Cancer Res. 23, 6138–6150 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Smyth, M. J., Ngiow, S. F., Ribas, A. & Teng, M. W. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat. Rev. Clin. Oncol. 13, 143–158 (2016).

    CAS  PubMed  Google Scholar 

  243. Gharwan, H. & Groninger, H. Kinase inhibitors and monoclonal antibodies in oncology: clinical implications. Nat. Rev. Clin. Oncol. 13, 209–227 (2016).

    CAS  PubMed  Google Scholar 

  244. Ayyar, B. V., Arora, S. & O’Kennedy, R. Coming-of-age of antibodies in cancer therapeutics. Trends Pharmacol. Sci. 37, 1009–1028 (2016).

    CAS  PubMed  Google Scholar 

  245. Katoh, M. Combination immuno-oncology therapy with immune checkpoint blockers targeting PD-L1, PD-1 or CTLA4 and epigenetic drugs targeting MYC and immune evasion for precision medicine. J. Thorac. Dis. 10, 1294–1299 (2018).

    PubMed  PubMed Central  Google Scholar 

  246. Boussiotis, V. A. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med. 375, 1767–1778 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Sweis, R. F. et al. Molecular drivers of the non-T cell-inflamed tumor microenvironment in urothelial bladder cancer. Cancer Immunol. Res. 4, 563–568 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Palakurthi, S. et al. Improved survival with erdafitinib (JNJ-42756493) and PD-1 blockade mediated by enhancement of anti-tumor immunity in an FGFR2-driven genetically engineered mouse model of lung cancer. Cancer Immunol. Res. 5 (Suppl. 3), B27 (2017).

    Google Scholar 

  251. Lee, C. H. et al. Lenvatinib plus pembrolizumab in patients with renal cell carcinoma: updated results. J. Clin. Oncol. 36 (Suppl. 15), 4560 (2018).

    Google Scholar 

  252. Makker, V. et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: updated results. J. Clin. Oncol. 36 (Suppl.), 5596 (2018).

    Google Scholar 

  253. Lin, J. et al. Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): preliminary data and correlation with next-generation sequencing. J. Clin. Oncol. 36 (Suppl. 4), 500 (2018).

    Google Scholar 

  254. Baselga, J. et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379, 633–640 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  255. Janjigian, Y. Y. et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 4, 1036–1045 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Crystal, A. S. et al. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science 346, 1480–1486 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Allen, J. M. et al. Genomic profiling of circulating tumor DNA in relapsed EGFR-mutated lung adenocarcinoma reveals an acquired FGFR3-TACC3 fusion. Clin. Lung Cancer 18, e219–e222 (2017).

    CAS  PubMed  Google Scholar 

  258. Traer, E. et al. FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia. Cancer Res. 76, 6471–6482 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Cao, Z. et al. Molecular checkpoint decisions made by subverted vascular niche transform indolent tumor cells into chemoresistant cancer stem cells. Cancer Cell 31, 110–126 (2017).

    CAS  PubMed  Google Scholar 

  260. Li, Q. et al. Paracrine fibroblast growth factor initiates oncogenic synergy with epithelial FGFR/Src transformation in prostate tumor progression. Neoplasia 20, 233–243 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Hoeflich, K. BLU-554, a novel, potent and selective inhibitor of FGFR4 for the treatment of liver cancer. Presented at the 50th International Liver Cancer Congress in Vienna, Austria (22–26 Apr 2015).

  262. Futami, T. et al. ASP5878, a novel inhibitor of FGFR1, 2, 3, and 4, inhibits the growth of FGF19-expressing hepatocellular carcinoma. Mol. Cancer Ther. 16, 68–75 (2017).

    CAS  PubMed  Google Scholar 

  263. Porta, C., Giglione, P., Liguigli, W. & Paglino, C. Dovitinib (CHIR258, TKI258): structure, development and preclinical and clinical activity. Future Oncol. 11, 39–50 (2015).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a grant-in-aid from M. Katoh’s Fund for the Knowledge-Base Project.

Author information

Authors and Affiliations

  1. Department of Omics Network, National Cancer Center, 5-1-1 Tsukiji, Chuo ward, Tokyo, Japan

    Masaru Katoh

Authors
  1. Masaru Katoh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masaru Katoh.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Publisher’s note

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Katoh, M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol 16, 105–122 (2019). https://doi.org/10.1038/s41571-018-0115-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-018-0115-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing