Department of Pharmacology and Neuroscience.
Department of Biomedical Sciences, and.
JCI Insight. 2023 Dec 22;8(24):e171140. doi: 10.1172/jci.insight.171140.
The widely used chemotherapy cisplatin causes permanent hearing loss in 40%-60% of patients with cancer. One drug, sodium thiosulfate, is approved by the FDA for use in pediatric patients with localized solid tumors for preventing cisplatin-induced hearing loss, but more drugs are desperately needed. Here, we tested dabrafenib, an FDA-approved BRAF kinase inhibitor and anticancer drug, in a clinically relevant multidose cisplatin mouse model. The protective effects of dabrafenib, given orally twice daily with cisplatin, were determined by functional hearing tests and cochlear outer hair cell counts. Toxicity of the drug cotreatment was evaluated, and levels of phosphorylated ERK were measured. A dabrafenib dose of 3 mg/kg BW, twice daily, in mice, was determined to be the minimum effective dose, and it is equivalent to one-tenth of the daily FDA-approved dose for human cancer treatment. The levels of hearing protection acquired, 20-25 dB at the 3 frequencies tested, in both female and male mice, persisted for 4 months after completion of treatments. Moreover, dabrafenib exhibited a good in vivo therapeutic index (> 25), protected hearing in 2 mouse strains, and diminished cisplatin-induced weight loss. This study demonstrates that dabrafenib is a promising candidate drug for protection from cisplatin-induced hearing loss.
广泛使用的化疗药物顺铂会导致 40%-60%的癌症患者永久性听力损失。一种名为硫代硫酸钠的药物已被 FDA 批准用于局部实体肿瘤的儿科患者，以预防顺铂引起的听力损失，但仍迫切需要更多的药物。在这里，我们在一个临床相关的多剂量顺铂小鼠模型中测试了达拉非尼，这是一种已获 FDA 批准的 BRAF 激酶抑制剂和抗癌药物。通过功能听力测试和耳蜗外毛细胞计数来确定达拉非尼与顺铂联合使用的保护作用。评估了药物联合治疗的毒性，并测量了磷酸化 ERK 的水平。确定了每天两次口服 3 毫克/千克体重的达拉非尼剂量是最小有效剂量，相当于人类癌症治疗每日 FDA 批准剂量的十分之一。在接受治疗 4 个月后，在两种性别小鼠中，在测试的 3 个频率下，听力保护水平持续了 20-25dB。此外，达拉非尼表现出良好的体内治疗指数（>25），可保护两种小鼠品系免受顺铂引起的听力损失，并减轻顺铂引起的体重减轻。这项研究表明，达拉非尼是一种很有前途的预防顺铂引起的听力损失的候选药物。
