BRAF inhibition protects against hearing loss in mice

Matthew A. Ingersoll, Emma A. Malloy, Lauryn E. Caster, Eva M. Holland, Zhenhang Xu, Marisa Zallocchi, Duane Currier, Huizhan Liu, David Z.Z. He, Jaeki Min, Taosheng Chen, Jian Zuo, Tal Teitz

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbereabd0561
JournalScience Advances
Volume6
Issue number49
DOIs
StatePublished - Dec 2 2020

All Science Journal Classification (ASJC) codes

  • General

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