Journal
SCIENCE ADVANCES
Volume 6, Issue 49, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abd0561
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Funding
- Nebraska Biomedical Research Development Fund [LB692]
- Bellucci Foundation For Translational Hearing Research
- NIDCD NIH/SBIR [1R43DC018463]
- DCI Reserve Funds Project [C-4160]
- American Hearing Research Foundation
- ONR [N00014-18-1-2507]
- ALSAC
- Dr. and Mrs. R. Ferlic Research Undergraduate Fellowship
- [R01DC015444]
- [R01DC015010]
- [USAMRMC-RH170030]
- [P30CA21765]
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Hearing loss caused by noise, aging, antibiotics, and chemotherapy affects 10% of the world population, yet there are no Food and Drug Administration (FDA)-approved drugs to prevent it. Here, we screened 162 small-molecule kinase-specific inhibitors for reduction of cisplatin toxicity in an inner ear cell line and identified dabrafenib (TAFINLAR), a BRAF kinase inhibitor FDA-approved for cancer treatment. Dabrafenib and six additional kinase inhibitors in the BRAF/MEK/ERK cellular pathway mitigated cisplatin-induced hair cell death in the cell line and mouse cochlear explants. In adult mice, oral delivery of dabrafenib repressed ERK phosphorylation in cochlear cells, and protected from cisplatin- and noise-induced hearing loss. Full protection was achieved in mice with co-treatment with oral AZD5438, a CDK2 kinase inhibitor. Our study explores a previously unidentified cellular pathway and molecular target BRAF kinase for otoprotection and may advance dabrafenib into clinics to benefit patients with cisplatin- and noise-induced ototoxicity.
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