KSR1 Knockout Mouse Model Demonstrates MAPK Pathway's Key Role in Cisplatin- and Noise-induced Hearing Loss.

Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise-induced permanent hearing loss compared with their wild-type KSR1 littermates. KSR1 is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK1/2 and ERK1/2 and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells.

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

Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise-induced permanent hearing loss compared to their wild-type KSR1 littermates. KSR1 is expressed in the cochlea and is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK and ERK and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells.

Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI.

Significance Statement: To combat both untoward effects of nephrotoxicity and ototoxicity in cisplatin-treated patients, two potential therapeutic oral anticancer drugs AZD5438 and dabrafenib, a phase-2 clinical trial protein kinase CDK2 inhibitor and an US Food and Drug Administration-approved drug BRAF inhibitor, respectively, were tested in an established mouse AKI model. Both drugs have previously been shown to protect significantly against cisplatin-induced hearing loss in mice. Each drug ameliorated cisplatin-induced increases in the serum biomarkers BUN, creatinine, and neutrophil gelatinase-associated lipocalin.