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C11, a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor, suppresses breast cancer metastasis and angiogenesis

Acta Pharmacologica Sinica (2018) | Download Citation

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Abstract

The fibroblast growth factor receptors (FGFRs) are increasingly considered attractive targets for therapeutic cancer intervention due to their roles in tumor metastasis and angiogenesis. Here, we identified a new selective FGFR inhibitor, C11, and assessed its antitumor activities. C11 was a selective FGFR1 inhibitor with an IC50 of 19 nM among a panel of 20 tyrosine kinases. C11 inhibited cell proliferation in various tumors, particularly bladder cancer and breast cancer. C11 also inhibited breast cancer MDA-MB-231 cell migration and invasion via suppression of FGFR1 phosphorylation and its downstream signaling pathway. Suppression of matrix metalloproteinases 2/9 (MMP2/9) was associated with the anti-motility activity of C11. Furthermore, the anti-angiogenesis activity of C11 was verified in endothelial cells and chicken chorioallantoic membranes (CAMs). C11 inhibited the migration and tube formation of HMEC-1 endothelial cells and inhibited angiogenesis in a CAM assay. In sum, C11 is a novel selective FGFR1 inhibitor that exhibits potent activity against breast cancer metastasis and angiogenesis.

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References

  1. 1.

    Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer. 2017;17:318–32.

  2. 2.

    Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr-Relat Cancer. 2000;7:165–97.

  3. 3.

    Tomlinson DC, Lamont FR, Shnyder SD, Knowles MA. Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer. Cancer Res. 2009;69:4613–20.

  4. 4.

    Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. WIREs Dev Biol. 2015;4:215–66.

  5. 5.

    Acevedo VD, Ittmann M, Spencer DM. Paths of FGFR-driven tumorigenesis. Cell Cycle. 2009;8:580–8.

  6. 6.

    Itoh N, Ornitz DM. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J Biochem. 2011;149:121–30.

  7. 7.

    Tiseo M, Gelsomino F, Alfieri R, Cavazzoni A, Bozzetti C, De Giorgi AM, et al. FGFR as potential target in the treatment of squamous non small cell lung cancer. Cancer Treat Rev. 2015;41:527–39.

  8. 8.

    Perez-Garcia J, Munoz-Couselo E, Soberino J, Racca F, Cortes J. Targeting FGFR pathway in breast cancer. Breast. 2018;37:126–33.

  9. 9.

    Li XQ, Guise CP, Taghipouran R, Yosaatmadja Y, Ashoorzadeh A, Paik WK, 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. 2017;135:531–43.

  10. 10.

    Brameld KA, Owens TD, Verner E, Venetsanakos E, Bradshaw JM, Phan VT, et al. Discovery of the irreversible covalent FGFR inhibitor 8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the treatment of solid tumors. J Med Chem. 2017;60:6516–27.

  11. 11.

    Wang Y, Li L, Fan J, Dai Y, Jiang A, Geng M, et al. Discovery of potent irreversible pan-Fibroblast Growth Factor Receptor (FGFR) inhibitors. J Med Chem. 2018. https://doi.org/10.1021/acs.jmedchem.7b01843

  12. 12.

    Angevin E, Lopez-Martin JA, Lin CC, Gschwend JE, Harzstark A, Castellano D, et al. Phase I study of Dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. Clin Cancer Res. 2013;19:1257–68.

  13. 13.

    Bello E, Colella G, Scarlato V, Oliva P, Berndt A, Valbusa G, et al. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011;71:1396–405.

  14. 14.

    Yeung KT, Cohen EEW. Lenvatinib in advanced, radioactive Iodine-refractory, differentiated thyroid carcinoma. Clin Cancer Res. 2015;21:5420–6.

  15. 15.

    Gozgit JM, Wong MJ, Moran L, Wardwell S, Mohemmad QK, Narasimhan NI, et al. Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther. 2012;11:690–9.

  16. 16.

    Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, et al. BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774–82.

  17. 17.

    Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, et al. AZD4547: An orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012;72:2045–56.

  18. 18.

    Guagnano V, Kauffmann A, Wohrle S, Stamm C, Ito M, Barys L, et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov. 2012;2:1118–33.

  19. 19.

    Perera TPS, Jovcheva E, Mevellec L, Vialard J, De Lange D, Verhulst T, et al. Discovery and pharmacological characterization of JNJ-42756493 (Erdafitinib), a functionally selective small-molecule FGFR family inhibitor. Mol Cancer Ther. 2017;16:1010–20.

  20. 20.

    Ebiike H, Taka N, Matsushita M, Ohmori M, Takami K, Hyohdoh I, et al. Discovery of [5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]- (1H-indol-2-yl)methanone (CH5183284/Debio 1347), an orally available and selective Fibroblast Growth Factor Receptor (FGFR) inhibitor. J Med Chem. 2016;59:10586–600.

  21. 21.

    Zhao GS, Li WY, Chen DH, Henry JR, Li HY, Chen ZG, 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;10:2200–10.

  22. 22.

    Chen Z, Wang X, Zhu WP, Cao XW, Tong LJ, Li HL, et al. Acenaphtho[1,2-b]pyrrole-based selective fibroblast growth factor receptors 1 (FGFR1) inhibitors: Design, synthesis, and biological activity. J Med Chem. 2011;54:3732–45.

  23. 23.

    Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 1998;17:5896–904.

  24. 24.

    Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, et al. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem. 2004;47:1750–9.

  25. 25.

    Li MY, Lv YC, Lj Tong, Peng T, Qu R, Zhang T, et al. DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo. Acta Pharmacol Sin. 2017;37:398–407.

  26. 26.

    Liu YQ, Wang YN, Lu XY, Tong LJ, Li Y, Zhang T, et al. Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R. Acta Pharmacol Sin. 2018. https://doi.org/10.1038/s41401-018-0056-0

  27. 27.

    Mohammadi M, McMahon G, Sun L, Tang C, Hirth P, Yeh BK, et al. Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science. 1997;276:955–60.

  28. 28.

    Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: Analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22:259–67.

  29. 29.

    Fantozzi A, Christofori G. Mouse models of breast cancer metastasis. Breast Cancer Res. 2006;8:212 https://doi.org/10.1186/bcr1530

  30. 30.

    Brady N, Chuntova P, Bade LK, Schwertfeger KL. The FGF/FGFR axis as a therapeutic target in breast cancer. Expert Rev. Endocrinol Metab. 2013;8:391–402.

  31. 31.

    Marcus N, Christian F, Burkhard K, Frieder B, Seibel MJ. Site-specific human breast cancer (MDA-MB-231) metastases in nude rats: Model characterisation and in vivo effects of ibandronate on tumour growth. Int J Cancer. 2003;107:468–77.

  32. 32.

    Tauro M, Lynch CC. Cutting to the chase: how matrix metalloproteinase-2 activity controls breast-cancer-to-bone metastasis. Cancers. 2018;10. https://doi.org/10.3390/cancers10060185

  33. 33.

    Cihoric N, Savic S, Schneider S, Ackermann I, Bichsel-Naef M, Schmid RA, et al. Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer. Brit J Cancer. 2014;110:2914–22.

  34. 34.

    Weiss J, Sos ML, Seidel D, Peifer M, Zander T, Heuckmann JM, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med. 2010;2:62ra93.

  35. 35.

    Yang W, Yao YW, Zeng JL, Liang WJ, Wang L, Bai CQ, et al. Prognostic value of FGFR1 gene copy number in patients with non-small cell lung cancer: a meta-analysis. J Thorac Dis. 2014;6:803–9.

  36. 36.

    Reis JS, Simpson PT, Turner NC, Lambros MB, Jones C, Mackay A, et al. FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin Cancer Res. 2006;12:6652–62.

  37. 37.

    Courjal F, Cuny M, Simony-Lafontaine J, Louason G, Speiser P, Zeillinger R, et al. Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: Definition of phenotypic groups. Cancer Res. 1997;57:4360–7.

  38. 38.

    Lee HJ, Seo AN, Park SY, Kim JY, Park JY, Yu JH, et al. Low prognostic implication of fibroblast growth factor family activation in triple-negative breast cancer subsets. Ann Surg Oncol. 2014;21:1561–8.

  39. 39.

    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. Ca-Cancer J Clin. 2011;61:69–90.

  40. 40.

    Hase T, Kawashiri S, Tanaka A, Nozaki S, Noguchi N, Kato K, et al. Correlation of basic fibroblast growth factor expression with the invasion and the prognosis of oral squamous cell carcinoma. J Oral Pathol Med. 2006;35:136–9.

  41. 41.

    Sato T, Oshima T, Yoshihara K, Yamamoto N, Yamada R, Nagano Y, et al. Overexpression of the fibroblast growth factor receptor-1 gene correlates with liver metastasis in colorectal cancer. Oncol Rep. 2009;21:211–6.

  42. 42.

    Blair KJ, Kiang A, Wang-Rodriguez J, Yu MA, Doherty JK. Ongkeko WMEGF and bFGF promote invasion that is modulated by PI3/Akt kinase and Erk in vestibular schwannoma. Otol Neurotol. 2011;32:308–14.

  43. 43.

    Jezierska A, Motyl T. Matrix Metalloproteinase-2 involvement in breast cancer progression: a mini-review. Med Sci Monit. 2009;15:Ra32–40.

  44. 44.

    Cathcart J, Pulkoski-Gross A, Cao J. Targeting matrix metalloproteinases in cancer: Bringing new Life to old ideas. Genes Dis. 2015;2:26–34.

  45. 45.

    Li H, Qiu ZW, Li F, Wang CL. The relationship between MMP-2 and MMP-9 expression levels with breast cancer incidence and prognosis. Oncol Lett. 2017;14:5865–70.

  46. 46.

    Coussens LM, Fingleton B, Matrisian LM. Cancer therapy - Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science. 2002;295:2387–92.

  47. 47.

    Tauro M, McGuire J, Lynch CC. New approaches to selectively target cancer-associated matrix metalloproteinase activity. Cancer Metast Rev. 2014;33:1043–57.

  48. 48.

    Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth F R. 2005;16:159–78.

  49. 49.

    Auguste P, Gursel DB, Lemiere S, Reimers D, Cuevas P, Carceller F, et al. Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and -independent mechanisms. Cancer Res. 2001;61:1717–26.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (grants 81173080, 81321092, 21236002 and 21302054), the National Basic Research Program of China (973 Program, 2010CB126100), the National High Technology Research and Development Program of China (863 Program, 2011AA10A207), the National Science & Technology Pillar Program (2009ZX09103–102), the Shanghai Committee of Science and Technology (grant 13ZR1453100) and the Fundamental Research Funds for the Central Universities.

Author contributions

JD, HX, Y-FX, X-HQ and H-LL designed research; ZC, L-JT, B-YT, H-YL, XW, TZ and YC performed research; ZC, XW and X-WC contributed new reagents or analytic tools; HX and ZC analyzed data; HX and ZC wrote the paper.

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Affiliations

  1. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    • Zhuo Chen
    • , Lin-jiang Tong
    • , Bai-you Tang
    • , Hong-yan Liu
    • , Tao Zhang
    • , Yi Chen
    • , Hua Xie
    •  & Jian Ding
  2. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China

    • Zhuo Chen
    • , Xin Wang
    • , Xian-wen Cao
    • , Hong-lin Li
    • , Xu-hong Qian
    •  & Yu-fang Xu

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Competing interests

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

Corresponding authors

Correspondence to Yu-fang Xu or Hua Xie or Jian Ding.

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https://doi.org/10.1038/s41401-018-0191-7