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

Oncogene volume 37, pages 5682–5693 (2018)Cite this article

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Abstract

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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Acknowledgements

This work was supported by the Thyssen Foundation (Grant No.: 10.16.1.028MN 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.

Authors and Affiliations

  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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  1. Kristina Golfmann
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Corresponding author

Correspondence to Roland T. Ullrich.

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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.

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Golfmann, K., Meder, L., Koker, M. et al. Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1-amplified breast cancer. Oncogene 37, 5682–5693 (2018). https://doi.org/10.1038/s41388-018-0380-3

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