Investigational fibroblast growth factor receptor 2 antagonists in early phase clinical trials to treat solid tumors

References

• Touat M, Ileana E, Postel-Vinay S, et al. Targeting FGFR signaling in cancer. Clin Cancer Res off J Am Assoc Cancer Res. 2015;21(12):2684–2694.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Adjei AA. Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. Oncologist. 2015;20(6):660–673.
   PubMed Web of Science ®Google Scholar
• Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10(2):116–129.
   PubMed Web of Science ®Google Scholar
• Carter EP, Fearon AE, Grose RP. Careless talk costs lives: fibroblast growth factor receptor signalling and the consequences of pathway malfunction. Trends Cell Biol. 2015;25(4):221–233.
   PubMed Web of Science ®Google Scholar
• Li P, Huang T, Zou Q, et al. FGFR2 promotes expression of PD-L1 in colorectal cancer via the JAK/STAT3 signaling pathway. J Iimmunol. 2019;202(10):3065–3075.
   PubMed Web of Science ®Google Scholar
• Pond AC, Herschkowitz JI, Schwertfeger KL, et al. Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer. Cancer Res. 2010;70(12):4868–4879.
   PubMed Web of Science ®Google Scholar
• Su N, Jin M, Chen L. Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models. Bone Res. 2014;2:14003.
   PubMed Web of Science ®Google Scholar
• Carter JH, Cottrell CE, McNulty SN, et al. FGFR2 amplification in colorectal adenocarcinoma. Mol Case Studies. 2017;3(6):a001495.
   Google Scholar
• Matsumoto K, Arao T, Hamaguchi T, et al. FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer. 2012;106(4):727–732.
   PubMed Web of Science ®Google Scholar
• Gartside MG, Chen H, Ibrahimi OA, et al. Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma. Mol Cancer Res. 2009;7(1):41–54.
   PubMed Web of Science ®Google Scholar
• Ishiwata T. Role of fibroblast growth factor receptor-2 splicing in normal and cancer cells. Front Biosci. 2018;23:626–639.
   PubMed Web of Science ®Google Scholar
• Matsuda Y, Hagio M, Seya T, et al. Fibroblast growth factor receptor 2 IIIc as a therapeutic target for colorectal cancer cells. Mol Cancer Ther. 2012;11(9):2010–2020.
   PubMed Web of Science ®Google Scholar
• Matsuda Y, Ishiwata T, Yamahatsu K, et al. Overexpressed fibroblast growth factor receptor 2 in the invasive front of colorectal cancer: a potential therapeutic target in colorectal cancer. Cancer Lett. 2011;309(2):209–219.
   PubMed Web of Science ®Google Scholar
• Vanmechelen M, Lambrechts D, Van Brussel T, et al. Fibroblast growth factor receptor-2 polymorphism rs2981582 is correlated with progression-free survival and overall survival in patients with metastatic clear-cell renal cell carcinoma treated with sunitinib. Clin Genitourin Cancer. 2019;17(2):e235–e246.
   PubMed Web of Science ®Google Scholar
• Easton DF, Pooley KA, Dunning AM, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447(7148):1087–1093.
   PubMed Web of Science ®Google Scholar
• Lei H, Deng CX. Fibroblast growth factor receptor 2 signaling in breast cancer. Int J Biol Sci. 2017;13(9):1163–1171.
   PubMed Web of Science ®Google Scholar
• Ahmad SM, Bhattacharyya P, Jeffries N, et al. Two forkhead transcription factors regulate cardiac progenitor specification by controlling the expression of receptors of the fibroblast growth factor and Wnt signaling pathways. Development. 2016;143(2):306–317.
   PubMed Web of Science ®Google Scholar
• Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer. 2000;7(3):165–197.
   PubMed Web of Science ®Google Scholar
• Gong SG. Isoforms of receptors of fibroblast growth factors. J Cell Physiol. 2014;229(12):1887–1895.
   PubMed Web of Science ®Google Scholar
• Alonso-Gordoa T, Garcia-Bermejo ML, Grande E, et al. Targeting tyrosine kinases in renal cell carcinoma: “New bullets against old guys”. Int J Mol Sci. 2019;20(8):1901.
   Web of Science ®Google Scholar
• Porebska N, Latko M, Kucinska M, et al. Targeting cellular trafficking of fibroblast growth factor receptors as a strategy for selective cancer treatment. J Clin Med. 2018;8(1):7.
   Web of Science ®Google Scholar
• Boichuk S, Galembikova A, Dunaev P, et al. Targeting of FGF-signaling re-sensitizes Gastrointestinal Stromal Tumors (GIST) to imatinib In Vitro and In Vivo. Molecules. 2018;23(10):2643.
   Web of Science ®Google Scholar
• Cho K, Ishiwata T, Uchida E, et al. Enhanced expression of keratinocyte growth factor and its receptor correlates with venous invasion in pancreatic cancer. Am J Pathol. 2007;170(6):1964–1974.
   PubMed Web of Science ®Google Scholar
• Tamaru N, Hishikawa Y, Ejima K, et al. Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer. Lab Invest. 2004;84(11):1460–1471.
   PubMed Web of Science ®Google Scholar
• Orr-Urtreger A, Bedford MT, Burakova T, et al. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev Biol. 1993;158(2):475–486.
   PubMed Web of Science ®Google Scholar
• Ohashi R, Matsuda Y, Ishiwata T, et al. Downregulation of fibroblast growth factor receptor 2 and its isoforms correlates with a high proliferation rate and poor prognosis in high-grade glioma. Oncol Rep. 2014;32(3):1163–1169.
   PubMed Web of Science ®Google Scholar
• Ornitz DM, Marie PJ. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 2015;29(14):1463–1486.
   PubMed Web of Science ®Google Scholar
• Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J. 2011;437(2):199–213.
   PubMed Web of Science ®Google Scholar
• Dorey K, Amaya E. FGF signalling: diverse roles during early vertebrate embryogenesis. Development. 2010;137(22):3731–3742.
   PubMed Web of Science ®Google Scholar
• Tomlinson DC, Knowles MA. Altered splicing of FGFR1 is associated with high tumor grade and stage and leads to increased sensitivity to FGF1 in bladder cancer. Am J Pathol. 2010;177(5):2379–2386.
   PubMed Web of Science ®Google Scholar
• Tanner Y, Grose RP, Dysregulated FGF signalling in neoplastic disorders. Semin Cell Dev Biol. 2016; 53:126–135
   PubMed Web of Science ®Google Scholar
• Helsten T, Elkin S, Arthur E, et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res off J Am Assoc Cancer Res. 2016;22(1):259–267.
   PubMed Web of Science ®Google Scholar
• Ornitz DM, Xu J, Colvin JS, et al. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996;271(25):15292–15297.
   PubMed Web of Science ®Google Scholar
• Knights V, Cook SJ. De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol Ther. 2010;125(1):105–117.
   PubMed Web of Science ®Google Scholar
• Finch PW, Rubin JS, Miki T, et al. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science. 1989;245(4919):752–755.
   PubMed Web of Science ®Google Scholar
• Savagner P, Valles AM, Jouanneau J, et al. Alternative splicing in fibroblast growth factor receptor 2 is associated with induced epithelial-mesenchymal transition in rat bladder carcinoma cells. Mol Biol Cell. 1994;5(8):851–862.
   PubMed Web of Science ®Google Scholar
• Yan G, Fukabori Y, McBride G, et al. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol Cell Biol. 1993;13(8):4513–4522.
   PubMed Web of Science ®Google Scholar
• Ong SH, Guy GR, Hadari YR, et al. FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Mol Cell Biol. 2000;20(3):979–989.
   PubMed Web of Science ®Google Scholar
• Lew ED, Furdui CM, Anderson KS, et al. The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations. Sci Signal. 2009;2(58):ra6.
   PubMed Web of Science ®Google Scholar
• Peng WC, Lin X, Torres J. The strong dimerization of the transmembrane domain of the fibroblast growth factor receptor (FGFR) is modulated by C-terminal juxtamembrane residues. Protein Sci. 2009;18(2):450–459.
   PubMed Web of Science ®Google Scholar
• Dudka AA, Sweet SM, Heath JK. Signal transducers and activators of transcription-3 binding to the fibroblast growth factor receptor is activated by receptor amplification. Cancer Res. 2010;70(8):3391–3401.
   PubMed Web of Science ®Google Scholar
• Chang MM, Lai MS, Hong SY, et al. FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells. Cancer Sci. 2018;109(11):3503–3518.
   PubMed Web of Science ®Google Scholar
• Huang T, Liu D, Wang Y, et al. FGFR2 promotes gastric cancer progression by inhibiting the expression of thrombospondin4 via PI3K-Akt-Mtor pathway. Cell Physiol Biochem. 2018;50(4):1332–1345.
   PubMedGoogle Scholar
• Huang Y, Hamana T, Liu J, et al. Type 2 fibroblast growth factor receptor signaling preserves stemness and prevents differentiation of prostate stem cells from the basal compartment. J Biol Chem. 2015;290(29):17753–17761.
   PubMed Web of Science ®Google Scholar
• Goyal L, Shi L, Liu LY, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discovery. 2019;9(8):1064–1079.
   PubMedGoogle Scholar
• Chen J, Bell J, Lau BT, et al. A functional CRISPR/Cas9 screen identifies kinases that modulate FGFR inhibitor response in gastric cancer. Oncogenesis. 2019;8(5):33.
   PubMedGoogle Scholar
• Harding MJ, Nechiporuk AV. Fgfr-Ras-MAPK signaling is required for apical constriction via apical positioning of Rho-associated kinase during mechanosensory organ formation. Development. 2012;139(17):3130–3135.
   PubMed Web of Science ®Google Scholar
• Turner N, Lambros MB, Horlings HM, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene. 2010;29(14):2013–2023.
   PubMed Web of Science ®Google Scholar
• Ajani JA, Lee J, Sano T, et al. Gastric adenocarcinoma. Nat Rev Dis Primers. 2017;3:17036.
   PubMed Web of Science ®Google Scholar
• Su X, Zhan P, Gavine PR, et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer. 2014;110(4):967–975.
   PubMed Web of Science ®Google Scholar
• Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med Res Rev. 2014;34(2):280–300.
   PubMed Web of Science ®Google Scholar
• Turczyk L, Kitowska K, Mieszkowska M, et al. FGFR2-driven signaling counteracts tamoxifen effect on ERalpha-positive breast cancer cells. Neoplasia. 2017;19(10):791–804.
   PubMed Web of Science ®Google Scholar
• Huang YL, Chou WC, Hsiung CN, et al. FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis. Hum Mol Genet. 2015;24(12):3506–3517.
   PubMed Web of Science ®Google Scholar
• Kunstlinger H, Fassunke J, Schildhaus HU, et al. FGFR2 is overexpressed in myxoid liposarcoma and inhibition of FGFR signaling impairs tumor growth in vitro. Oncotarget. 2015;6(24):20215–20230.
   PubMedGoogle Scholar
• Zhang K, Chu K, Wu X, et al. Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma. Cancer Res. 2013;73(4):1298–1307.
   PubMed Web of Science ®Google Scholar
• Gautam P, Jaiswal A, Aittokallio T, et al. Phenotypic screening combined with machine learning for efficient identification of breast cancer-selective therapeutic targets. Cell chemical biology. 2019.
   Google Scholar
• Dankova Z, Zubor P, Marian G, et al. Predictive accuracy of the breast cancer genetic risk model based on eight common genetic variants: the BACkSIDE study. J Biotechnol. 2019;299:1–7.
   PubMed Web of Science ®Google Scholar
• Campbell TM, Castro MAA, de Oliveira KG, et al. ERalpha binding by transcription factors NFIB and YBX1 enables FGFR2 signaling to modulate estrogen responsiveness in breast cancer. Cancer Res. 2018;78(2):410–421.
   PubMed Web of Science ®Google Scholar
• Greer SU, Nadauld LD, Lau BT, et al. Linked read sequencing resolves complex genomic rearrangements in gastric cancer metastases. Genome Med. 2017;9(1):57.
   PubMedGoogle Scholar
• Jang J, Kim HK, Bang H, et al. Antitumor effect of AZD4547 in a fibroblast growth factor receptor 2-amplified gastric cancer patient-derived cell model. Transl Oncol. 2017;10(4):469–475.
   PubMed Web of Science ®Google Scholar
• Kim SY, Ahn T, Bang H, et al. Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion. Oncotarget. 2017;8(9):15014–15022.
   PubMedGoogle Scholar
• Cancer Genome Atlas Research N, Kandoth C, Schultz N. et al., Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.
   PubMed Web of Science ®Google Scholar
• Byron SA, Gartside M, Powell MA, et al. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features. PloS One. 2012;7(2):e30801.
   PubMed Web of Science ®Google Scholar
• Tsimafeyeu I, Khasanova A, Stepanova E, et al. FGFR2 overexpression predicts survival outcome in patients with metastatic papillary renal cell carcinoma. Clin Transl Oncol. 2017;19(2):265–268.
   PubMed Web of Science ®Google Scholar
• Byron SA, Chen H, Wortmann A, et al. The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors. Neoplasia. 2013;15(8):975–988.
   PubMed Web of Science ®Google Scholar
• Hibi M, Kaneda H, Tanizaki J, et al. FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib. Cancer Sci. 2016;107(11):1667–1676.
   PubMed Web of Science ®Google Scholar
• Sakai K, Ukita M, Schmidt J, et al. Clonal composition of human ovarian cancer based on copy number analysis reveals a reciprocal relation with oncogenic mutation status. Cancer Lett. 2017;405:22–28.
   PubMed Web of Science ®Google Scholar
• Jeske YW, Ali S, Byron SA, et al. FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: an NRG oncology/gynecologic oncology group study. Gynecol Oncol. 2017;145(2):366–373.
   PubMed Web of Science ®Google Scholar
• Kim DH, Kwak Y, Kim ND, et al. Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations. Cancer Biol Ther. 2016;17(1):65–78.
   PubMed Web of Science ®Google Scholar
• Valle JW, Lamarca A, Goyal L, et al. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017;7(9):943–962.
   PubMed Web of Science ®Google Scholar
• Ahn SM, Jang SJ, Shim JH, et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology. 2014;60(6):1972–1982.
   PubMed Web of Science ®Google Scholar
• Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist. 2014;19(3):235–242.
   PubMed Web of Science ®Google Scholar
• Williams SV, Hurst CD, Knowles MA. Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet. 2013;22(4):795–803.
   PubMed Web of Science ®Google Scholar
• Singh D, Chan JM, Zoppoli P, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science. 2012;337(6099):1231–1235.
   PubMed Web of Science ®Google Scholar
• Papadopoulos KP, El-Rayes BF, Tolcher AW, et al. A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br J Cancer. 2017;117(11):1592–1599.
   PubMed Web of Science ®Google Scholar
• Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3(6):636–647.
   PubMed Web of Science ®Google Scholar
• Krook MA, Barker H, Chen HZ, et al. Characterization of a KLK2-FGFR2 fusion gene in two cases of metastatic prostate cancer. Prostate cancer and prostatic diseases. 2019. doi:10.1038.
   Google Scholar
• Porta R, Borea R, Coelho A, et al. FGFR a promising druggable target in cancer: molecular biology and new drugs. Crit Rev Oncol Hematol. 2017;113:256–267.
   PubMed Web of Science ®Google Scholar
• Schramm K, Iskar M, Statz B, et al. DECIPHER pooled shRNA library screen identifies PP2A and FGFR signaling as potential therapeutic targets for DIPGs. Neuro Oncol. 2019:pii:noz057. doi:10.1093.
   PubMed Web of Science ®Google Scholar
• Gozgit JM, Wong MJ, Moran L, et al. Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther. 2012;11(3):690–699.
   PubMed Web of Science ®Google Scholar
• Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Lancet Haematol. 2018;5(12):e618–e627.
   PubMed Web of Science ®Google Scholar
• Tojo A, Kyo T, Yamamoto K, et al. Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study. Int J Hematol. 2017;106(3):385–397.
   PubMed Web of Science ®Google Scholar
• Dhillon S. Nintedanib: a review of its use as second-line treatment in adults with advanced non-small cell lung cancer of adenocarcinoma histology. Target Oncol. 2015;10(2):303–310.
   PubMed Web of Science ®Google Scholar
• Patwardhan PP, Musi E, Schwartz GK. Preclinical evaluation of nintedanib, a triple angiokinase inhibitor, in soft-tissue sarcoma: potential therapeutic implication for synovial sarcoma. Mol Cancer Ther. 2018;17(11):2329–2340.
   PubMed Web of Science ®Google Scholar
• Hilberg F, Tontsch-Grunt U, Baum A, 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. 2018;364(3):494–503.
   PubMed Web of Science ®Google Scholar
• Alshangiti A, Chandhoke G, Ellis PM. Antiangiogenic therapies in non-small-cell lung cancer. Current Oncol. 2018;25(1):S45–S58.
   PubMed Web of Science ®Google Scholar
• Otsubo K, Kishimoto J, Kenmotsu H, et al. Treatment rationale and design for J-SONIC: a randomized study of carboplatin plus nab-paclitaxel with or without nintedanib for advanced non-small-cell lung cancer with idiopathic pulmonary fibrosis. Clin Lung Cancer. 2018;19(1):e5–e9.
   PubMed Web of Science ®Google Scholar
• Quintela-Fandino M, Apala JV, Malon D, et al. Nintedanib plus letrozole in early breast cancer: a phase 0/I pharmacodynamic, pharmacokinetic, and safety clinical trial of combined FGFR1 and aromatase inhibition. BCR. 2019;21(1):69.
   PubMedGoogle Scholar
• Yeung KT, Cohen EE. Lenvatinib in advanced, radioactive iodine-refractory, differentiated thyroid carcinoma. Clin Cancer Res off J Am Assoc Cancer Res. 2015;21(24):5420–5426.
   PubMed Web of Science ®Google Scholar
• Hoshi T, Watanabe Miyano S, Watanabe H, et al. Lenvatinib induces death of human hepatocellular carcinoma cells harboring an activated FGF signaling pathway through inhibition of FGFR-MAPK cascades. Biochem Biophys Res Commun. 2019;513(1):1–7.
   PubMed Web of Science ®Google Scholar
• Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014;6:18.
   PubMedGoogle Scholar
• Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PloS One. 2019;14(2):e0212513.
   PubMed Web of Science ®Google Scholar
• Kiyota N, Robinson B, Shah M, et al. Defining radioiodine-refractory differentiated thyroid cancer: efficacy and safety of lenvatinib by radioiodine-refractory criteria in the select Trial. Thyroid. 2017;27(9):1135–1141.
   PubMed Web of Science ®Google Scholar
• Scott LJ. Lenvatinib: first global approval. Drugs. 2015;75(5):553–560.
   PubMed Web of Science ®Google Scholar
• Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621–630.
   PubMed Web of Science ®Google Scholar
• Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–1173.
   PubMed Web of Science ®Google Scholar
• Gianoukakis AG, Dutcus CE, Batty N, et al. Prolonged duration of response in lenvatinib responders with thyroid cancer. Endocr Relat Cancer. 2018;25(6):699–704.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473–1482.
   PubMed Web of Science ®Google Scholar
• Nishio M, Horai T, Horiike A, et al. Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer. Br J Cancer. 2013;109(3):538–544.
   PubMed Web of Science ®Google Scholar
• Plantamura I, Casalini P, Dugnani E, et al. PDGFRbeta and FGFR2 mediate endothelial cell differentiation capability of triple negative breast carcinoma cells. Mol Oncol. 2014;8(5):968–981.
   PubMed Web of Science ®Google Scholar
• Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–513.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584–3590.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–124.
   PubMed Web of Science ®Google Scholar
• Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–1338.
   PubMed Web of Science ®Google Scholar
• Wang L, Ding Y, Wei L, et al. Recurrent olfactory neuroblastoma treated with cetuximab and sunitinib: a case report. Medicine (Baltimore). 2016;95(18):e3536.
   PubMed Web of Science ®Google Scholar
• Sonpavde G, Hutson TE, Sternberg CN. Pazopanib for the treatment of renal cell carcinoma and other malignancies. Drugs Today. 2009;45(9):651–661.
   PubMed Web of Science ®Google Scholar
• van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879–1886.
   PubMed Web of Science ®Google Scholar
• Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–1068.
   PubMed Web of Science ®Google Scholar
• Todo M, Shirotake S, Nishimoto K, et al. Usefulness of Implementing Comprehensive Pharmaceutical Care for Metastatic Renal Cell Carcinoma Outpatients Treated with Pazopanib. Anticancer Res. 2019;39(2):999–1004.
   PubMed Web of Science ®Google Scholar
• Bellmunt J, Lalani AA, Jacobus S, et al. Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma. Br J Cancer. 2018;119(6):707–712.
   PubMed Web of Science ®Google Scholar
• Porta C, Giglione P, Liguigli W, et al. Dovitinib (CHIR258, TKI258): structure, development and preclinical and clinical activity. Future Oncol. 2015;11(1):39–50.
   PubMed Web of Science ®Google Scholar
• Kahkonen TE, Tuomela JM, Gronroos TJ, et al. Dovitinib dilactic acid reduces tumor growth and tumor-induced bone changes in an experimental breast cancer bone growth model. J Bone Oncol. 2019;16:100232.
   PubMed Web of Science ®Google Scholar
• Andre F, Bachelot T, Campone M, et al. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res off J Am Assoc Cancer Res. 2013;19(13):3693–3702.
   PubMed Web of Science ®Google Scholar
• Eritja N, Domingo M, Dosil MA, et al. Combinatorial therapy using dovitinib and ICI182.780 (fulvestrant) blocks tumoral activity of endometrial cancer cells. Mol Cancer Ther. 2014;13(4):776–787.
   PubMed Web of Science ®Google Scholar
• Zhang H, Hylander BL, LeVea C, et al. Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models. Br J Cancer. 2014;110(2):320–329.
   PubMed Web of Science ®Google Scholar
• Konecny GE, Finkler N, Garcia AA, 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. 2015;16(6):686–694.
   PubMed Web of Science ®Google Scholar
• Choi YJ, Kim HS, Park SH, et al. Phase II study of dovitinib in patients with castration-resistant prostate cancer (KCSG-GU11–05). Cancer Res Treat. 2018;50(4):1252–1259.
   PubMedGoogle Scholar
• Chila R, Hall GT, Abbadessa G, et al. Multi-chemotherapeutic schedules containing the pan-FGFR inhibitor ARQ 087 are safe and show antitumor activity in different xenograft models. Transl Oncol. 2017;10(2):153–157.
   PubMed Web of Science ®Google Scholar
• Yu Y, Hall T, Eathiraj S, et al. In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor. Anticancer Drugs. 2017;28(5):503–513.
   PubMed Web of Science ®Google Scholar
• Hall TG, Yu Y, Eathiraj S, et al. Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation. PloS One. 2016;11(9):e0162594.
   PubMed Web of Science ®Google Scholar
• Mazzaferro V, El-Rayes BF, Droz Dit Busset M, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120(2):165–171.
   PubMed Web of Science ®Google Scholar
• Guan Z, Lan H, Sun D, et al. A potential novel therapy for FGFR1-amplified pancreatic cancer with bone metastasis, screened by next-generation sequencing and a patient-derived xenograft model. Oncol Lett. 2019;17(2):2303–2307.
   PubMed Web of Science ®Google Scholar
• Zhang J, Zhang L, Su X, et al. Translating the therapeutic potential of AZD4547 in FGFR1-amplified non-small cell lung cancer through the use of patient-derived tumor xenograft models. Clin Cancer Res off J Am Assoc Cancer Res. 2012;18(24):6658–6667.
   PubMed Web of Science ®Google Scholar
• Gavine PR, Mooney L, Kilgour E, et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012;72(8):2045–2056.
   PubMed Web of Science ®Google Scholar
• Packer LM, Stehbens SJ, Bonazzi VF, et al. Bcl-2 inhibitors enhance FGFR inhibitor-induced mitochondrial-dependent cell death in FGFR2-mutant endometrial cancer. Mol Oncol. 2019;13(4):738–756.
   PubMed Web of Science ®Google Scholar
• Kwak Y, Cho H, Hur W, et al. Antitumor Effects and Mechanisms of AZD4547 on FGFR2-deregulated endometrial cancer cells. Mol Cancer Ther. 2015;14(10):2292–2302.
   PubMed Web of Science ®Google Scholar
• Yao TJ, Zhu JH, Peng DF, et al. AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells. Tumour Biol. 2015;36(7):5641–5648.
   PubMedGoogle Scholar
• Xie L, Su X, Zhang L, et al. FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin Cancer Res off J Am Assoc Cancer Res. 2013;19(9):2572–2583.
   PubMed Web of Science ®Google Scholar
• Luo H, Quan J, Xiao H, et al. FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelialmesenchymal transition to gefitinib. Oncol Rep. 2018;39(5):2270–2278.
   PubMed Web of Science ®Google Scholar
• Lau WM, Teng E, Huang KK, et al. Acquired resistance to FGFR inhibitor in diffuse-type gastric cancer through an AKT-independent PKC-mediated phosphorylation of GSK3beta. Mol Cancer Ther. 2018;17(1):232–242.
   PubMed Web of Science ®Google Scholar
• Pearson A, Smyth E, Babina IS, et al. High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial. Cancer Discov. 2016;6(8):838–851.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Bang YJ, Mansoor W, 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. 2017;28(6):1316–1324.
   PubMed Web of Science ®Google Scholar
• Okuno T, Yashiro M, Masuda G, et al. Establishment of a new scirrhous gastric cancer cell line with FGFR2 overexpression, OCUM-14. Ann Surg Oncol. 2019;26(4):1093–1102.
   PubMed Web of Science ®Google Scholar
• Nogova L, Sequist LV, Perez Garcia JM, 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. 2017;35(2):157–165.
   PubMed Web of Science ®Google Scholar
• Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-Altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36(3):276–282.
   PubMed Web of Science ®Google Scholar
• Goyal L, Saha SK, Liu LY, et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov. 2017;7(3):252–263.
   PubMed Web of Science ®Google Scholar
• Byron SA, Gartside MG, Wellens CL, et al. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. Cancer Res. 2008;68(17):6902–6907.
   PubMed Web of Science ®Google Scholar
• Packer LM, Geng X, Bonazzi VF, et al. PI3K inhibitors synergize with FGFR inhibitors to enhance antitumor responses in FGFR2(mutant) endometrial cancers. Mol Cancer Ther. 2017;16(4):637–648.
   PubMed Web of Science ®Google Scholar
• Hanes R, Grad I, Lorenz S, et al. Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma. Oncotarget. 2016;7(34):54583–54595.
   PubMedGoogle Scholar
• Cattin S, Ramont L, Ruegg C. Characterization and in vivo validation of a three-dimensional multi-cellular culture model to study heterotypic interactions in colorectal cancer cell growth, invasion and metastasis. Front Bioeng Biotechnol. 2018;6:97.
   PubMed Web of Science ®Google Scholar
• Verstraete M, Debucquoy A, Gonnissen A, et al. In vitro and in vivo evaluation of the radiosensitizing effect of a selective FGFR inhibitor (JNJ-42756493) for rectal cancer. BMC Cancer. 2015;15:946.
   PubMed Web of Science ®Google Scholar
• Nishina T, Takahashi S, Iwasawa R, 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. 2018;36(3):424–434.
   PubMed Web of Science ®Google Scholar
• Tabernero J, Bahleda R, Dienstmann R, 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. 2015;33(30):3401–3408.
   PubMed Web of Science ®Google Scholar
• Nakanishi Y, Akiyama N, Tsukaguchi T, 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. 2014;13(11):2547–2558.
   PubMed Web of Science ®Google Scholar
• Voss MH, Hierro C, Heist RS, et al. A phase I, open-label, multicenter, dose-escalation study of the oral selective FGFR inhibitor debio 1347 in patients with advanced solid tumors harboring FGFR gene alterations. Clin Cancer Res off J Am Assoc Cancer Res. 2019;25(9):2699–2707.
   PubMed Web of Science ®Google Scholar
• Goyal L, Shi L, Liu LY, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov. 2019;9(8):1064–1079.
   PubMed Web of Science ®Google Scholar
• Nakatsuru Y, Ochiiwa H, Sootome H, et al. Abstract A272: intermittent treatment with TAS-120, an irreversible FGFR inhibitor, is effective in tumors harboring a FGFR gene abnormality. Mol Cancer Ther. 2013;12(11_Supplement):A272–A272.
   Web of Science ®Google Scholar
• Kalyukina M, Yosaatmadja Y, Middleditch MJ, et al. TAS-120 cancer target binding: defining reactivity and revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) irreversible structure. ChemMedChem. 2019;14(4):494–500.
   PubMed Web of Science ®Google Scholar
• Wu D, Guo M, Philips MA, et al. Crystal structure of the FGFR4/LY2874455 complex reveals insights into the Pan-FGFR selectivity of LY2874455. PloS One. 2016;11(9):e0162491.
   PubMed Web of Science ®Google Scholar
• Hanes R, Munthe E, Grad I, et al. Preclinical evaluation of the Pan-FGFR inhibitor LY2874455 in FRS2-Amplified liposarcoma. Cells. 2019;8(2):pii:E189. doi:10.3390.
   PubMed Web of Science ®Google Scholar
• Hagel M, Miduturu C, Sheets M, et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov. 2015;5(4):424–437.
   PubMed Web of Science ®Google Scholar
• Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220–231.
   PubMed Web of Science ®Google Scholar
• Zhao G, Li WY, Chen D, et al. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol Cancer Ther. 2011;10(11):2200–2210.
   PubMed Web of Science ®Google Scholar
• Michael M, Bang YJ, Park YS, et al. A phase 1 study of LY2874455, an oral selective pan-FGFR inhibitor, in patients with advanced cancer. Target Oncol. 2017;12(4):463–474.
   PubMed Web of Science ®Google Scholar
• Sommer A, Kopitz C, Schatz CA, et al. Preclinical efficacy of the auristatin-based antibody-drug conjugate BAY 1187982 for the treatment of FGFR2-positive solid tumors. Cancer Res. 2016;76(21):6331–6339.
   PubMed Web of Science ®Google Scholar
• Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 2002;16(12):1446–1465.
   PubMed Web of Science ®Google Scholar
• Fogarty MP, Emmenegger BA, Grasfeder LL, et al. Fibroblast growth factor blocks Sonic hedgehog signaling in neuronal precursors and tumor cells. Proc Natl Acad Sci U S A. 2007;104(8):2973–2978.
   PubMed Web of Science ®Google Scholar
• Naimi B, Latil A, Fournier G, et al. Down-regulation of (IIIb) and (IIIc) isoforms of fibroblast growth factor receptor 2 (FGFR2) is associated with malignant progression in human prostate. Prostate. 2002;52(3):245–252.
   PubMed Web of Science ®Google Scholar
• Matsunobu T, Ishiwata T, Yoshino M, et al. Expression of keratinocyte growth factor receptor correlates with expansive growth and early stage of gastric cancer. Int J Oncol. 2006;28(2):307–314.
   PubMed Web of Science ®Google Scholar
• Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–1134.
   PubMed Web of Science ®Google Scholar
• Bellot F, Crumley G, Kaplow JM, et al. Ligand-induced transphosphorylation between different FGF receptors. Embo J. 1991;10(10):2849–2854.
   PubMed Web of Science ®Google Scholar
• Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol. 2019;16(2):105–122.
   PubMed Web of Science ®Google Scholar