@article{dcc6a604596e4a83ac407b008ef2e2c1,
title = "BRAF inhibition protects against hearing loss in mice",
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.",
author = "Ingersoll, {Matthew A.} and Malloy, {Emma A.} and Caster, {Lauryn E.} and Holland, {Eva M.} and Zhenhang Xu and Marisa Zallocchi and Duane Currier and Huizhan Liu and He, {David Z.Z.} and Jaeki Min and Taosheng Chen and Jian Zuo and Tal Teitz",
note = "Funding Information: We thank H. Feng for technical assistance, D. F. Kresock for help in preparing the manuscript, and P. Steyger, L. Hansen, P. Swanson, P. Abel, T. Kaur, S. Vijayakumar, S. D. Pezhman, and all members of the Translational Hearing Center at Creighton University for inspiring discussions. We thank Z. Rankovic and B. Freeman for expert advice and C. Howe, J. Gelineauvan Waes, P. Steele, A. Bryen, and the Creighton University ARF staff for assistance with the mouse studies. This research was funded by the following grants: LB692 Nebraska Biomedical Research Development Fund, Bellucci Foundation For Translational Hearing Research, NIDCD NIH/SBIR 1R43DC018463, DCI Reserve Funds Project C4160, and American Hearing Research Foundation grant to T.T.; R01DC015444, R01DC015010, ONR N000141812507, USAMRMCRH170030, LB692, ALSAC, and P30CA21765 (St. Jude) to J.Z.; and Dr. and Mrs. R. Ferlic Research Undergraduate Fellowship to L.E.C.",
year = "2020",
month = dec,
day = "2",
doi = "10.1126/sciadv.abd0561",
language = "English (US)",
volume = "6",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "49",
}