Dabrafenib protects from cisplatin-induced hearing loss in a clinically relevant mouse model

Abstract

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.

KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss

“…MAPK signaling has been implicated in cisplatin and noise-induced hearing loss [6][7][8]10,11 , and here we show that the KSR1 KO mice do not have cochlear structural abnormalities and exhibit normal hearing before damage; therefore, utilization of the KSR1 KO mouse model can help elucidate the role of the MAPK pathway in noise and cisplatin-induced hearing loss while germline knockouts of RAF, MEK, and ERK are embryonically lethal 26 .…”

“…Previous studies indicate inhibition of the MAPK pathway by dabrafenib confers protection from cisplatin-induced hearing loss and we sought to determine whether genetic KO of KSR1 and suppression of the pathway provides similar protection 6,8 . Initially, baseline ABR thresholds were determined for P42 KSR1 WT and KO mice, mice were allowed to recover for 7 days and then administered a single, high-dose intraperitoneal injection of cisplatin of 18 mg/kg, an optimized dose for hearing loss in C57/BL/6 mice.…”

“…Other laboratories have also demonstrated that activation of the MAPK pathway occurs after ototoxic insult and targeting this pathway can be a therapeutic approach to protect from hearing loss [9][10][11][12][13][14][15] . Dabrafenib, a BRAF inhibitor, is a promising otoprotective drug in preclinical studies which has been studied by our laboratory 6,8 . Dabrafenib, which is well tolerated by patients, is already FDA approved for cancer treatment which makes it a promising compound to repurpose for protection from cisplatin and noise-induced hearing loss 16,17 .…”

Oseltamivir (Tamiflu), a Commonly Prescribed Antiviral Drug, Mitigates Hearing Loss in Mice

“…DPOAE recordings were collected from mice anesthetized as previously described (Ingersoll et al, 2024(Ingersoll et al, , 2023(Ingersoll et al, , 2020Lutze et al, 2023). DPOAE recordings were collected in a sound booth (Industrial Acoustic Company) using the ER10B+ microphone system, with ear tip and speaker tubes placed in the left ear canal such that the tympanic membrane remained unobstructed.…”

“…This suggests that targeting shared molecular pathways could protect from both insults of hearing loss. For example, we have shown that mitogen activated protein kinase (MAPK) pathway activation occurs with both cisplatin and damaging noise exposure in the supporting and hair cells of the inner ear, and multiple inhibitors of the MAPK pathway shield mice from both cisplatin-and noise-induced hearing loss (Ingersoll et al, 2024(Ingersoll et al, , 2023(Ingersoll et al, , 2020Lutze et al, 2023). In addition, molecular processes such as activation of shared programmed cell death pathways and enhanced inflammation with immune cell infiltration occur following both insults (Frye et al, 2019;He et al, 2020;Ramkumar et al, 2021;Wood and Zuo, 2017;Wu et al, 2020).…”