BRAF inhibition protects against hearing loss in mice.
Sci Adv
; 6(49)2020 12.
Article
en En
| MEDLINE
| ID: mdl-33268358
ABSTRACT
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Sordera
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Pérdida Auditiva
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Antineoplásicos
Tipo de estudio:
Etiology_studies
Límite:
Animals
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Humans
Idioma:
En
Año:
2020
Tipo del documento:
Article