BRAF inhibition protects against hearing loss in mice.

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

doi:10.1126/sciadv.abd0561

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.

Highlights

Seven hundred million people worldwide suffer from varying degrees of hearing loss [1, 2]
One hundred percent luminescence was defined by cells treated with cisplatin alone, and 0% was defined by untreated cells
Dabrafenib was selected for further characterization because it is orally bioavailable, Food and Drug Administration (FDA)-approved for treatment of metastatic melanoma and anaplastic thyroid cancer, and EU-approved for non–small cell lung carcinoma and because it can cross the bloodbrain barrier [15,16,17,18, 35, 36]

Summary

Introduction

Seven hundred million people worldwide suffer from varying degrees of hearing loss [1, 2]. Cisplatin chemotherapy results in hearing loss in 40 to 60% of patients with cancer and impedes the development of language skills in young individuals [3,4,5]. To date, there are no Food and Drug Administration (FDA)–approved drugs to protect from noise-, cisplatin-, antibiotic-, or age-related hearing loss. STS, a direct inactivator of cisplatin and an antioxidant, was successful at lowering incidence of hearing loss by 48% in children with localized standard-risk hepatoblastoma when administered 6 hours after cisplatin chemotherapy, but lowered survival rate of treated patients with disseminated tumors [7,8,9]. The steroid dexamethasone has been shown to be only partially effective in treating noise ototoxicity [10, 11]

Methods

Results

Conclusion