PUBLICATION
In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss
- Authors
- Vijayakumar, S., DiGuiseppi, J.A., Dabestani, P.J., Ryan, W.G., Quevedo, R.V., Li, Y., Diers, J., Tu, S., Fleegel, J., Nguyen, C., Rhoda, L.M., Imami, A.S., Hamoud, A.A., Lovas, S., McCullumsmith, R.E., Zallocchi, M., Zuo, J.
- ID
- ZDB-PUB-240620-29
- Date
- 2024
- Source
- Science advances 10: eadk2299 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Drug Evaluation, Preclinical
- Computer Simulation
- Animals
- Hearing Loss, Noise-Induced*/drug therapy
- Hearing Loss, Noise-Induced*/genetics
- Hearing Loss, Noise-Induced*/metabolism
- Zebrafish*
- ErbB Receptors*/antagonists & inhibitors
- ErbB Receptors*/genetics
- ErbB Receptors*/metabolism
- Mice
- Gene Expression Profiling
- Humans
- Protein Kinase Inhibitors/pharmacology
- Mice, Knockout
- Transcriptome*
- Disease Models, Animal
- PubMed
- 38896614 Full text @ Sci Adv
Citation
Vijayakumar, S., DiGuiseppi, J.A., Dabestani, P.J., Ryan, W.G., Quevedo, R.V., Li, Y., Diers, J., Tu, S., Fleegel, J., Nguyen, C., Rhoda, L.M., Imami, A.S., Hamoud, A.A., Lovas, S., McCullumsmith, R.E., Zallocchi, M., Zuo, J. (2024) In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss. Science advances. 10:eadk2299.
Abstract
Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration-approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. Further tests with EGFR knockout mice and EGF-morpholino zebrafish confirmed their protective role against NIHL. Molecular studies in mice highlighted EGFR's crucial involvement in NIHL and the protective effect of zorifertinib. When given orally, zorifertinib was found in the perilymph with favorable pharmacokinetics. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping