TY - JOUR
T1 - Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer
AU - Zlinska, Vladimira
AU - Feketova, Zuzana
AU - Czyrek, Aleksandra
AU - Chudzian, Julia
AU - Zivkovic, Martina Lenarcic
AU - Ursachi, Vlad Constantin
AU - Dudeja, Pooja
AU - Fafilek, Bohumil
AU - Rynes, Jan
AU - Rico-Llanos, Gustavo
AU - Koudelka, Adolf
AU - Roy, Tanaya
AU - Biadun, Martyna
AU - Raskova, Vendula
AU - Svozilova, Katerina
AU - Stroblova, Michaela
AU - Krzyscik, Mateusz
AU - Hristova, Kalina
AU - Krowarsch, Daniel
AU - Foldynova-Trantirkova, Silvie
AU - Zakrzewska, Malgorzata
AU - Trantirek, Lukas
AU - Krejci, Pavel
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2025/3/11
Y1 - 2025/3/11
N2 - 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.
AB - 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.
KW - DNA aptamer
KW - FGFR signaling
KW - FGFR1
KW - MT: Oligonucleotides: Therapies and Applications
KW - craniosynostosis
KW - extracellular domain
KW - inhibitor
KW - skeletal dysplasia
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U2 - 10.1016/j.omtn.2024.102405
DO - 10.1016/j.omtn.2024.102405
M3 - Article
C2 - 39759879
AN - SCOPUS:85211617850
SN - 2162-2531
VL - 36
JO - Molecular Therapy Nucleic Acids
JF - Molecular Therapy Nucleic Acids
IS - 1
M1 - 102405
ER -