Abstract 6767: Apurinic/apyrimidinic endonuclease 2 (APE2) mediates cisplatin ototoxicity by triggering MYH9-dependent mitochondrial toxicity in outer hair cells
Authors: Eric Irons, Qingzhu Wang, Wanying Zhang, Fangfang Zhao, Mei Yin, Belinda Willard, Qing Zheng, Bohua Hu, Jordan Beach, Richard Prayson, Jennifer Yu, Jianhong Lin, Jianjun Zhao
Journal: Cancer Research (2025)

Abstract Platinum compounds remain the backbone of chemotherapy regimens for a variety of solid tumors, despite their well-described adverse effects of nephrotoxicity, ototoxicity, and neurotoxicity. Cisplatin ototoxicity results from damage to the cochlear outer hair cells and remains a key dose-limiting toxicity in pediatric cancers, where its incidence reaches as high as 90% in testicular cancer patients. However, the mechanistic underpinnings of cisplatin ototoxicity remains incompletely understood and no treatments exist to prevent its onset. Here we describe a novel pathway mediating cisplatin-induced cell death in outer hair cells dependent on the base excision repair (BER) enzyme apurinic/apyrimidinic endonuclease 2 (APE2). APE2 was highly expressed in cochlear hair cells of patients with cisplatin ototoxicity compared to healthy controls. This was reproduced in vitro, where cisplatin rapidly upregulated APE2 expression and promoted its movement into the mitochondria within hours. APE2 suppressed the activation of ATR and p53 in response to cisplatin, instead promoting the mitochondrial translocation of p53 and intrinsic apoptosis. Knockdown of APE2 protected hair cells from cisplatin-induced apoptotic and non-apoptotic cell death in vitro. In a tamoxifen-induced Cre-lox transgenic mouse model, selective APE2 overexpression in cochlear outer hair cells resulted in loss of outer hair cells, disruption of cochlear architecture, and high-frequency hearing loss. Remarkably, this hearing loss was completely abrogated in mice that also harbored a knockout of MYH9, a non-muscle myosin that is mutated in rare genetic syndromes with hearing loss. We have observed MYH9 to be a binding partner of APE2 and now report that a specific interaction with the proximal coiled-coil domain of MYH9, adjacent to binding sites of its regulatory light chains, mediates this interaction. Consistent with the role of MYH9 in suppressing mitochondrial fission, we found that APE2 incapacitated oxidative phosphorylation and contributed to smaller, fragmented mitochondria. Our data demonstrate a novel mechanism in which the non-canonical DNA repair enzyme APE2 triggers cell death by inhibiting the DNA damage response and triggering MYH9-mediated mitochondrial damage, leading to the cochlear hair cell damage responsible for cisplatin ototoxicity. This work highlights a new therapeutic approach of targeting APE2 to mitigate the off-target toxicities associated with platinum medications. Citation Format: Eric Irons, Qingzhu Wang, Wanying Zhang, Fangfang Zhao, Mei Yin, Belinda Willard, Qing Zheng, Bohua Hu, Jordan Beach, Richard Prayson, Jennifer Yu, Jianhong Lin, Jianjun Zhao. Apurinic/apyrimidinic endonuclease 2 (APE2) mediates cisplatin ototoxicity by triggering MYH9-dependent mitochondrial toxicity in outer hair cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6767.