Golfmann, Kristina, Meder, Lydia ORCID: 0000-0002-9547-5812, Koker, Mirjam, Volz, Caroline, Borchmann, Sven, Tharun, Lars, Dietlein, Felix, Malchers, Florian, Florin, Alexandra, Buettner, Reinhard, Rosen, Neal, Rodrik-Outmezguine, Vanessa, Hallek, Michael and Ullrich, Roland T. (2018). Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1-amplified breast cancer. Oncogene, 37 (42). S. 5682 - 5694. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Golfmann, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meder, LydiaUNSPECIFIEDorcid.org/0000-0002-9547-5812UNSPECIFIED
Koker, MirjamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volz, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borchmann, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tharun, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietlein, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malchers, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosen, NealUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodrik-Outmezguine, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, Roland T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-169167
DOI: 10.1038/s41388-018-0380-3
Journal or Publication Title: Oncogene
Volume: 37
Number: 42
Page Range: S. 5682 - 5694
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5594
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACQUIRED-RESISTANCE; CARCINOMA-CELLS; GROWTH; RECEPTOR; ACTIVATION; SURVIVAL; BGJ398; TUMORS; AKTMultiple languages
Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16916

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