Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE 68178, USA.
Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA.
Sci Adv. 2020 Dec 2;6(49). doi: 10.1126/sciadv.abd0561. Print 2020 Dec.
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.
噪音、衰老、抗生素和化疗引起的听力损失影响了全球 10%的人口，但目前还没有获得美国食品和药物管理局 (FDA) 批准的药物来预防这种情况。在这里，我们筛选了 162 种小分子激酶特异性抑制剂，以减少内耳细胞系中顺铂的毒性，并确定了达拉非尼（TAFINLAR），一种用于癌症治疗的 BRAF 激酶抑制剂，已获得 FDA 批准。达拉非尼和细胞内 BRAF/MEK/ERK 通路中的另外六种激酶抑制剂减轻了细胞系和小鼠耳蜗外植体中的顺铂诱导的毛细胞死亡。在成年小鼠中，达拉非尼的口服给药抑制了耳蜗细胞中的 ERK 磷酸化，并能预防顺铂和噪声引起的听力损失。用 CDK2 激酶抑制剂 AZD5438 进行联合治疗的小鼠则能完全免受顺铂和噪声诱导的耳毒性影响。我们的研究探索了一种以前未被识别的细胞内途径和分子靶标 BRAF 激酶，用于耳保护，可能会将达拉非尼推进临床，造福于顺铂和噪声引起的耳毒性患者。
