Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy

Abstract

Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin‐induced ototoxicity remains unclear, and hearing preservation during cisplatin‐based chemotherapy in patients is lacking. We found activation of the ATM ‐Chk2‐p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin‐induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer hair cell death and inner hair cell survival. Encouragingly, however, genetic or pharmacological ablation of p53 substantially attenuated cochlear cell apoptosis, thus preserving hearing. Importantly, systemic administration of a p53 inhibitor in mice bearing patient‐derived triple‐negative breast cancer protected auditory function, without compromising the anti‐tumor efficacy of cisplatin. Altogether, these findings highlight a novel and effective strategy for hearing protection in cisplatin‐based chemotherapy. image The normal tissue injuries induced by the chemotherapeutic drug cisplatin remain a major clinical problem. Here, PFT ‐α is shown to protect hearing without compromising the chemotherapeutic efficacy of cisplatin, and even sensitizes TP 53 ‐mutant breast tumors to cisplatin. Activation of the ATM ‐Chk2‐p53 pathway by genotoxic stress is the major determinant of cisplatin ototoxicity. Targeting this signaling pathway through genetic or pharmacological ablation of p53 attenuates cochlear hair cell death and preserves hearing function during cisplatin treatment. Efficient hearing protection was achieved through local intratympanic injection of PFT ‐α, a suitable method for clinical practice in any type of cisplatin‐based cancer therapy. Systemic administration of cisplatin, combined with PFT ‐α, efficiently protects against hearing loss without compromising chemotherapeutic efficacy and even sensitizes TP 53 ‐mutant triple‐negative breast tumors to CDDP .