Role of MCT6 in mediating cisplatin-induced ototoxicity

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ABSTRACT Cisplatin is one of the most widely used anti-cancer drugs, however up to 70% of patients can suffer from severe dose-limiting ototoxicity. Platinum-mediated hearing loss is detrimental to the early speech development of children and can impede neurocognitive abilities, social integration, and financial status. Therefore, the long- term goal associated with this proposal is to assess the role of membrane transporters in regulating damage to cochlear cells following accumulation of cisplatin or its metabolites. The overall objective of this proposal is to delineate the involvement of the monocarboxylate transporter, MCT6, in mediating cisplatin-induced hearing loss. The central hypothesis is that MCT6 promotes uptake of an N-acetylcysteine S-conjugate metabolite of cisplatin (NAC-1) resulting in severe damage to cochlear hair cells and loss of hearing. The rationale for this project is that a predicted reduced functional genetic variant of MCT6 (rs4788863) was previously associated with lower rates of cisplatin-induced ototoxicity. Evaluating the mechanism by which MCT6 contributes to cisplatin-mediated hearing loss is necessary to address whether pharmacological inhibition of this transporter would be protective of an adverse event that has no current curative or preventative measures. The central hypothesis will be tested by pursuing two specific aims: 1) Investigate the ability of MCT6 to transport NAC-1; and 2) Determine the protective effect of MCT6-deficiency on cisplatin-induced ototoxicity in vivo. Under the first aim, in vitro models with high expression of MCT6 will be used to measure the ability of this transporter to modulate uptake of NAC-1 as well as cisplatin. Additionally, the influence of the rs478863 genetic variant, or pharmacological inhibition of MCT6, on platinum uptake or cytotoxicity will be assessed. Under the second aim, a MCT6-deficient in vivo mouse model will be used to evaluate the severity of cisplatin-induced hearing loss in the absence of the MCT6 transporter. Moreover, we will measure pharmacokinetic changes of cisplatin in MCT6- deficient mice. This will provide mechanistic insight into the role of MCT6 in the handling of cisplatin or its metabolites. The research proposed in this application is innovative because it represents a substantive departure from the status quo by evaluating the role MCT6 as a regulator of cochlear damage via facilitating accumulation of a toxic cisplatin metabolite. The proposed research is significant because it is expected to identify MCT6 as a transporter that can be pharmacologically targeted to reduce the severity of, or prevent, cisplatin-induced hearing loss associated with cancer therapy. Ultimately, such knowledge is predicted to reduce the number of patients who would experience significant social and economic challenges, including in young pediatric cancer survivors.