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

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Fibroblast growth factor receptor (FGFR) signaling plays a crucial role in various human conditions, including developmental disorders and cancer.
• Current therapeutic strategies targeting FGFRs rely on tyrosine kinase inhibitors (TKIs), which often lack specificity, inhibiting multiple FGFR variants and other kinases.
• This lack of specificity can lead to off-target effects and limit therapeutic efficacy.

Purpose of the Study:

• To identify and characterize a specific inhibitor for human fibroblast growth factor receptor 1 (FGFR1).
• To evaluate the potential of DNA aptamers as targeted therapeutics for FGFR1-related disorders.
• To investigate the mechanism of action and specificity of the identified FGFR1 inhibitor.

Main Methods:

• High-throughput screening to identify DNA aptamers targeting FGFR1.
• Biochemical assays to determine binding affinity (K_D) and specificity against various FGFR variants (FGFR1-4).
• Cell-based assays to assess the impact of the aptamer on downstream FGFR1 signaling pathways, cellular senescence, proliferation, and extracellular matrix homeostasis.

Main Results:

• A DNA aptamer, VZ23, was identified with high binding affinity for FGFR1b and FGFR1c, but not for other FGFR variants.
• VZ23 effectively inhibited FGFR1 signaling in cellular models, impacting senescence, proliferation, and extracellular matrix regulation.
• The aptamer's inhibitory activity was linked to its G-quadruplex structure, and it demonstrated specificity for FGFR1 over FGFR2-4.

Conclusions:

• DNA aptamers, such as VZ23, represent a promising class of targeted inhibitors for FGFR1.
• VZ23's specificity and mechanism of action suggest its potential as an alternative therapeutic strategy to TKIs for conditions involving impaired FGFR1 signaling, such as craniosynostosis.