Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer

Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer

Impaired fibroblast growth factor receptor (FGFR) signaling is associated with many human conditions, including growth disorders, degenerative diseases, and cancer. Current FGFR therapeutics are based on chemical inhibitors of FGFR tyrosine kinase activity (TKIs). However, FGFR TKIs are limited in t...

Full description

Saved in:
Bibliographic Details
Main Authors: Vladimira Zlinska, Zuzana Feketova, Aleksandra Czyrek, Julia Chudzian, Martina Lenarcic Zivkovic, Vlad-Constantin Ursachi, Pooja Dudeja, Bohumil Fafilek, Jan Rynes, Gustavo Rico-Llanos, Adolf Koudelka, Tanaya Roy, Martyna Biadun, Vendula Raskova, Katerina Svozilova, Michaela Stroblova, Mateusz Krzyscik, Kalina Hristova, Daniel Krowarsch, Silvie Foldynova-Trantirkova, Malgorzata Zakrzewska, Lukas Trantirek, Pavel Krejci
Format: Article
Language:English
Published: Elsevier 2025-03-01
Series:Molecular Therapy: Nucleic Acids
Subjects:
MT: Oligonucleotides: Therapies and Applications
FGFR signaling
FGFR1
inhibitor
DNA aptamer
extracellular domain
Online Access:http://www.sciencedirect.com/science/article/pii/S2162253124002920
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Impaired fibroblast growth factor receptor (FGFR) signaling is associated with many human conditions, including growth disorders, degenerative diseases, and cancer. Current FGFR therapeutics are based on chemical inhibitors of FGFR tyrosine kinase activity (TKIs). However, FGFR TKIs are limited in their target specificity as they generally inhibit all FGFRs and other receptor tyrosine kinases. In the search for specific inhibitors of human FGFR1, we identified VZ23, a DNA aptamer that binds to FGFR1b and FGFR1c with a KD of 55 nM and 162 nM, respectively, but not to the other FGFR variants (FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4). In cells, VZ23 inhibited the activation of downstream FGFR1 signaling and FGFR1-mediated regulation of cellular senescence, proliferation, and extracellular matrix homeostasis. Consistent with the specificity toward FGFR1 observed in vitro, VZ23 did not inhibit FGFR2-4 signaling in cells. We show that the VZ23 inhibits FGFR1 signaling in the presence of cognate fibroblast growth factor (FGF) ligands and its inhibitory activity is linked to its capacity to form unusual G-quadruplex structure. Our data suggest that targeting FGFR1 with DNA aptamers could be an effective alternative to TKIs for treating impaired FGFR1 signaling in human craniosynostoses.
ISSN:2162-2531

Similar Items