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Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1-amplified breast cancer

Oncogenevolume 37pages56825693 (2018) | Download Citation


FGFR1 amplification has been found in 15% of patients with breast cancer and has been postulated as a promising marker to predict response against FGFR inhibitors. However, early phase clinical trials of selective FGFR inhibitors demonstrated only limited efficacy in FGFR1-amplified breast cancer patients. We found that BGJ398, an FGFR inhibitor, effectively inhibited phosphorylation of FGFR1 and MEK/ERK signaling in FGFR1-amplified breast cancer without affecting tumor cell proliferation. However, FGFR1 knockout inhibited tumor angiogenesis in vivo. We unraveled that FGFR1 regulates the secretion of the proangiogenic vascular endothelial growth factor (VEGF) in a MAPK-dependent manner. We further found that FGF-FGFR1 signaling induces an autocrine activation of VEGF-VEGFR1 pathway that again amplifies VEGF secretion via VEGF-VEGFR1-AKT signaling. Targeting both VEGFR1 and FGFR1 resulted in synergistic anti-angiogenic treatment effects in vivo. We thus postulate synergistic treatment effects in FGFR1/VEGFR1-positive breast cancer patients by dual targeting of FGFR and VEGFR.

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This work was supported by the Thyssen Foundation (Grant No.: to RTU), by the Nachwuchsforschungsgruppen-NRW (Grant No.: 1411ng005 to RTU), by the Deutsche Forschungsgemeinschaft (DFG) (Grant No.: UL379/1-1 to RTU) and by the Deutsche Krebshilfe (Grant No.: 70113009 to RTU).

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Author notes

  1. These authors contributed equally: Kristina Golfmann, Lydia Meder.


  1. Department I of Internal Medicine, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany

    • Kristina Golfmann
    • , Lydia Meder
    • , Mirjam Koker
    • , Caroline Volz
    • , Sven Borchmann
    • , Michael Hallek
    •  & Roland T. Ullrich
  2. Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Straße 21, 50931, Cologne, Germany

    • Kristina Golfmann
    • , Lydia Meder
    • , Mirjam Koker
    • , Caroline Volz
    • , Sven Borchmann
    • , Reinhard Büttner
    • , Michael Hallek
    •  & Roland T. Ullrich
  3. German Hodgkin Study Group, Department I of Internal Medicine, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany

    • Sven Borchmann
  4. Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, 50931, Cologne, Germany

    • Sven Borchmann
    •  & Felix Dietlein
  5. Institute for Pathology, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany

    • Lars Tharun
    • , Alexandra Florin
    •  & Reinhard Büttner
  6. Department of Medical Oncology, Dana-Faber Cancer Institute, Boston, MA, 02215, USA

    • Felix Dietlein
  7. Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA

    • Felix Dietlein
  8. Department of Translational Genomics, University Hospital Cologne, Weyertal 115b, 50931, Cologne, Germany

    • Florian Malchers
  9. Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany

    • Florian Malchers
    • , Michael Hallek
    •  & Roland T. Ullrich
  10. Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    • Neal Rosen
    •  & Vanessa Rodrik-Outmezguine


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Conflict of interest

RTU received consulting fees from Novartis. FM received consulting fees from NEO NewOncology GmbH. VR-O is now a Novartis employee. The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Roland T. Ullrich.

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