Review Article | Published:

Fibroblast growth factor receptors as treatment targets in clinical oncology

Nature Reviews Clinical Oncology (2018) | Download Citation


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.

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  1. 1.

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

  2. 2.

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

  3. 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).

  4. 4.

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

  5. 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).

  6. 6.

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

  7. 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).

  8. 8.

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

  9. 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).

  10. 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).

  11. 11.

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

  12. 12.

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

  13. 13.

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

  14. 14.

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

  15. 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).

  16. 16.

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

  17. 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).

  18. 18.

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

  19. 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).

  20. 20.

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

  21. 21.

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

  22. 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).

  23. 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).

  24. 24.

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

  25. 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).

  26. 26.

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

  27. 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).

  28. 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).

  29. 29.

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

  30. 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).

  31. 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).

  32. 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).

  33. 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).

  34. 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).

  35. 35.

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

  36. 36.

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

  37. 37.

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

  38. 38.

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

  39. 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).

  40. 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).

  41. 41.

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

  42. 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).

  43. 43.

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

  44. 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).

  45. 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).

  46. 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).

  47. 47.

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

  48. 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).

  49. 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).

  50. 50.

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

  51. 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).

  52. 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).

  53. 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).

  54. 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).

  55. 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).

  56. 56.

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

  57. 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).

  58. 58.

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

  59. 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).

  60. 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).

  61. 61.

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

  62. 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).

  63. 63.

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

  64. 64.

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

  65. 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).

  66. 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).

  67. 67.

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

  68. 68.

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

  69. 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).

  70. 70.

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

  71. 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).

  72. 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).

  73. 73.

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

  74. 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).

  75. 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).

  76. 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).

  77. 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).

  78. 78.

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

  79. 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).

  80. 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).

  81. 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).

  82. 82.

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

  83. 83.

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

  84. 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).

  85. 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).

  86. 86.

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

  87. 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).

  88. 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).

  89. 89.

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

  90. 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).

  91. 91.

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

  92. 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).

  93. 93.

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

  94. 94.

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

  95. 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).

  96. 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).

  97. 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).

  98. 98.

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

  99. 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).

  100. 100.

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

  101. 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).

  102. 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).

  103. 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).

  104. 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).

  105. 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).

  106. 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).

  107. 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).

  108. 108.

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

  109. 109.

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

  110. 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).

  111. 111.

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

  112. 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).

  113. 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).

  114. 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).

  115. 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).

  116. 116.

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

  117. 117.

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

  118. 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).

  119. 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).

  120. 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).

  121. 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).

  122. 122.

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

  123. 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).

  124. 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).

  125. 125.

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

  126. 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).

  127. 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).

  128. 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).

  129. 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).

  130. 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).

  131. 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).

  132. 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).

  133. 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).

  134. 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).

  135. 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).

  136. 136.

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

  137. 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).

  138. 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).

  139. 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).

  140. 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).

  141. 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).

  142. 142.

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

  143. 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).

  144. 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).

  145. 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).

  146. 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).

  147. 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).

  148. 148.

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

  149. 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).

  150. 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).

  151. 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).

  152. 152.

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

  153. 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).

  154. 154.

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

  155. 155.

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

  156. 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).

  157. 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).

  158. 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).

  159. 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).

  160. 160.

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

  161. 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).

  162. 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).

  163. 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).

  164. 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).

  165. 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).

  166. 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).

  167. 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).

  168. 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).

  169. 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).

  170. 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).

  171. 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).

  172. 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).

  173. 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).

  174. 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).

  175. 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).

  176. 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).

  177. 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).

  178. 178.

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

  179. 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).

  180. 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).

  181. 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).

  182. 182.

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

  183. 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).

  184. 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).

  185. 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).

  186. 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. 187.

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

  188. 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).

  189. 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).

  190. 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).

  191. 191.

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

  192. 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).

  193. 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).

  194. 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).

  195. 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).

  196. 196.

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

  197. 197.

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

  198. 198.

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

  199. 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).

  200. 200.

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

  201. 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).

  202. 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).

  203. 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).

  204. 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).

  205. 205.

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

  206. 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).

  207. 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).

  208. 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).

  209. 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).

  210. 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).

  211. 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).

  212. 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).

  213. 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).

  214. 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).

  215. 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).

  216. 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).

  217. 217.

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

  218. 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).

  219. 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).

  220. 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).

  221. 221.

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

  222. 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).

  223. 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).

  224. 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).

  225. 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).

  226. 226.

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

  227. 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).

  228. 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).

  229. 229.

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

  230. 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).

  231. 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).

  232. 232.

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

  233. 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).

  234. 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).

  235. 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).

  236. 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).

  237. 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).

  238. 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).

  239. 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).

  240. 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).

  241. 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).

  242. 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).

  243. 243.

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

  244. 244.

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

  245. 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).

  246. 246.

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

  247. 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).

  248. 248.

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

  249. 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).

  250. 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).

  251. 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).

  252. 252.

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

  253. 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).

  254. 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).

  255. 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).

  256. 256.

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

  257. 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).

  258. 258.

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

  259. 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).

  260. 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).

  261. 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. 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).

  263. 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).

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

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

    • Masaru Katoh


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