| Literature DB >> 29970903 |
Kristina Golfmann1,2, Lydia Meder1,2, Mirjam Koker1,2, Caroline Volz1,2, Sven Borchmann1,2,3,4, Lars Tharun5, Felix Dietlein4,6,7, Florian Malchers8,9, Alexandra Florin5, Reinhard Büttner2,5, Neal Rosen10, Vanessa Rodrik-Outmezguine10, Michael Hallek1,2,9, Roland T Ullrich11,12,13.
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.Entities:
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Year: 2018 PMID： 29970903 DOI： 10.1038/s41388-018-0380-3
Source DB: PubMed Journal: Oncogene ISSN： 0950-9232 Impact factor: 9.867