Reversible p53 inhibition prevents cisplatinototoxicity without blocking chemotherapeutic efficacy.

Didier Decaudin,Domenico Maiorano,Jérôme Bourien,Jean‐Luc Puel,Julien Menardo,Florence François,Régis Nouvian,Nesrine Benkafadar,Jing Wang

doi:10.15252/emmm.201606230

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.

Highlights

Cisplatin (cis-diammine dichloroplatinum(II); CDDP) is a highly effective and widely used chemotherapeutic agent for the treatment of different types of human tumors, solid tumors (Siddik, 2003; Wang & Lippard, 2005)
Previous reports have shown that CDDP elicits a substantial loss of outer hair cells (OHCs) in the basal turn of the cochlea, with a lower impact on inner hair cells (IHCs) and no obvious effect on apical hair cells (Langer et al, 2013)
Previous studies revealed that in response to genotoxic stress, p53deficient tumor cells may arrest in the S and G2 phases via Chk1 activation to allow time for DNA repair and that Chk1 inhibitors selectively potentiate the effects of DNA-damaging agents, such as chemotherapy or radiation, in TP53-mutated cancer cells (Zhao et al, 2002; Ma et al, 2011)

Summary

Introduction

Cisplatin (cis-diammine dichloroplatinum(II); CDDP) is a highly effective and widely used chemotherapeutic agent for the treatment of different types of human tumors, solid tumors (Siddik, 2003; Wang & Lippard, 2005). In response to DNA damage, three major molecular sensors called ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3-related), and DNA-PK (DNA-dependent protein kinase) are recruited to the site of DNA damage, forming nuclear foci (Ciccia & Elledge, 2010; Smith et al, 2010). These sensors phosphorylate several proteins to induce the DNA damage response (Bassing et al, 2002; Celeste et al, 2002), in which p53, a major tumor suppressor, plays a pivotal role. Downstream of this response are targets which either promote cell survival or cause cells to undergo apoptosis (Shiloh, 2006; Di Micco et al, 2008)

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