Lutze Richard D, Ingersoll Matthew A, Kelmann Regina G, Teitz Tal
Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE 68178, USA.
bioRxiv. 2024 May 21:2024.05.20.595056. doi: 10.1101/2024.05.20.595056.
Hearing loss is one of the most common types of disability; however, there is only one FDA-approved drug to prevent any type of hearing loss. Treatment with the highly effective chemotherapy agent, cisplatin, and exposure to high decibel noises are two of the most common causes of hearing loss. The mitogen activated protein kinase (MAPK) pathway, a phosphorylation cascade consisting of RAF, MEK1/2, and ERK1/2, has been implicated in both types of hearing loss. Pharmacologically inhibiting BRAF or ERK1/2 is protective from noise and cisplatin-induced hearing loss in multiple mouse models. Trametinib, a MEK1/2 inhibitor, protects from cisplatin induced outer hair cell death in mouse cochlear explants; however, to the best of our knowledge, inhibiting MEK1/2 has not yet been shown to be protective from hearing loss . In this study, we demonstrate that trametinib protects from cisplatin-induced hearing loss in a translationally relevant mouse model and does not interfere with cisplatin's tumor killing efficacy in cancer cell lines. Higher doses of trametinib were toxic to mice when combined with cisplatin but lower doses of the drug were protective from hearing loss without any known toxicity. Trametinib also protected mice from noise-induced hearing loss and synaptic damage. This study shows that MEK1/2 inhibition protects from both insults of hearing loss and that targeting all three kinases in the MAPK pathway protect from cisplatin and noise-induced hearing loss in mice.
听力损失是最常见的残疾类型之一；然而，美国食品药品监督管理局（FDA）仅批准了一种药物可预防任何类型的听力损失。使用高效化疗药物顺铂进行治疗以及暴露于高分贝噪音中是导致听力损失的两个最常见原因。丝裂原活化蛋白激酶（MAPK）信号通路是一种由RAF、MEK1/2和ERK1/2组成的磷酸化级联反应，在这两种类型的听力损失中均有涉及。在多个小鼠模型中，通过药物抑制BRAF或ERK1/2可预防噪音和顺铂诱导的听力损失。曲美替尼是一种MEK1/2抑制剂，可保护小鼠耳蜗外植体免受顺铂诱导的外毛细胞死亡；然而，据我们所知，抑制MEK1/2尚未被证明可预防听力损失。在本研究中，我们证明曲美替尼在一个具有转化相关性的小鼠模型中可预防顺铂诱导的听力损失，并且不干扰顺铂在癌细胞系中的肿瘤杀伤效果。当与顺铂联合使用时，较高剂量的曲美替尼对小鼠有毒性，但较低剂量的该药物可预防听力损失且无任何已知毒性。曲美替尼还可保护小鼠免受噪音诱导的听力损失和突触损伤。本研究表明，抑制MEK1/2可预防两种听力损失损伤，并且靶向MAPK信号通路中的所有三种激酶可预防小鼠顺铂和噪音诱导的听力损失。
