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 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 K<sub>D</sub> 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 <i>in vitro</i>, 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.
Authors
- Kalina Hristova (ORCID: https://orcid.org/0000-0003-4274-4406)
- Martyna Biaduń (ORCID: https://orcid.org/0000-0002-2648-6593)
- Adolf Koudelka (ORCID: https://orcid.org/0000-0002-9998-8383)
- Silvie Foldynová-Trantírková (ORCID: https://orcid.org/0000-0001-8863-083X)
- Bohumil Fafílek (ORCID: https://orcid.org/0000-0002-3869-7937)
- Tanaya Roy (ORCID: https://orcid.org/0000-0003-0939-7158)
- Gustavo Rico-Llanos (ORCID: https://orcid.org/0000-0001-5991-848X)
- Jan Ryneš (ORCID: https://orcid.org/0000-0003-2091-390X)
- Vendula Rašková (ORCID: https://orcid.org/0000-0002-1746-1482)
- Pavel Krejčı́ (ORCID: https://orcid.org/0000-0003-0618-9134)
- Zuzana Feketová (ORCID: https://orcid.org/0000-0003-4620-4634)
- Katerina Svozilova
- Martina Lenarčič Živković (ORCID: https://orcid.org/0000-0001-6501-4145)
- Mateusz Adam Krzyścik (ORCID: https://orcid.org/0000-0002-9464-3829)
- Małgorzata Zakrzewska (ORCID: https://orcid.org/0000-0001-8214-1533)
- Lukáš Trantı́rek (ORCID: https://orcid.org/0000-0001-5948-4837)
- Julia Chudzian (ORCID: https://orcid.org/0000-0002-4146-953X)
- Daniel Krowarsch (ORCID: https://orcid.org/0000-0003-2856-218X)
- Aleksandra Czyrek (ORCID: https://orcid.org/0000-0002-8518-7075)
- Vlad-Constantin Ursachi (ORCID: https://orcid.org/0000-0002-8062-3595)
- Pooja Dudeja (ORCID: https://orcid.org/0009-0000-1564-2354)
- Vladimira Zlinska
- Michaela Stroblova
Institutions
- Central European Institute of Technology (CZ)
- Johns Hopkins University (US)
- Masaryk University (CZ)
- University of Wrocław (PL)
- Central European Institute of Technology – Masaryk University (CZ)
- Czech Academy of Sciences, Institute of Animal Physiology and Genetics (CZ)
- International Clinical Research Center, St. Anne's University Hospital Brno (CZ)
- National Institute of Biology (SI)
- National Institute of Chemistry (SI)
- Institute of Animal Physiology of the Slovak Academy of Sciences (SK)
Publication Details
- Journal
- Molecular Therapy — Nucleic Acids
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1016/j.omtn.2024.102405
- Citations
- 10
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- European Commission
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- Akademie Věd České Republiky
- Javna Agencija za Raziskovalno Dejavnost RS
- Agentura Pro Zdravotnický Výzkum České Republiky
- Masarykova Univerzita
- Lékařská fakulta, Masarykova univerzita
- European Regional Development Fund