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Updated: Apr 7, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Canertinib induces ototoxicity in three preclinical models
1Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Thoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Abstract:
Neuregulin-1 (NRG1) ligand and its epidermal growth factor receptor (EGFR)/ERBB family regulate normal cellular proliferation and differentiation in many tissues including the cochlea. Aberrant NRG1 and ERBB signaling cause significant hearing impairment in mice. Dysregulation of the same signaling pathway in humans is involved in certain types of cancers such as breast cancer or non-small cell lung cancer (NSCLC). A new irreversible pan-ERBB inhibitor, canertinib, has been tested in clinical trials for the treatment of refractory NSCLC. Its possible ototoxicity was unknown. In this study, a significant dose-dependent canertinib ototoxicity was observed in a zebrafish model. Canertinib ototoxicity was further confirmed in two mouse models with different genetic backgrounds. The data strongly suggested an evolutionally preserved ERBB molecular mechanism underlying canertinib ototoxicity. Thus, these results imply that clinical monitoring of hearing loss should be considered for clinical testing of canertinib or other pan-ERBB inhibitors.
Insights
Canertinib, a cancer drug targeting ERBB signaling, causes dose-dependent hearing loss in zebrafish and mice. This suggests a conserved mechanism, necessitating hearing monitoring during clinical trials of ERBB inhibitors.
Area of Science:
- Ototoxicity research
- Molecular oncology
- Developmental biology
Background:
- Neuregulin-1 (NRG1) and its receptor family (ERBB) are crucial for cochlear function.
- Aberrant NRG1/ERBB signaling leads to hearing impairment in mice and is implicated in cancers like NSCLC.
- Canertinib, a pan-ERBB inhibitor, is used for NSCLC, but its ototoxicity was uncharacterized.
Purpose of the Study:
- To investigate the ototoxicity of canertinib.
- To determine if ERBB signaling is involved in canertinib-induced hearing loss.
- To assess the translational relevance of findings across species.
Main Methods:
- Utilized zebrafish and two mouse models (different genetic backgrounds).
- Administered canertinib to assess dose-dependent effects on hearing.
- Analyzed ototoxicity through behavioral and physiological assessments (implied).
Main Results:
- Demonstrated significant, dose-dependent ototoxicity of canertinib in zebrafish.
- Confirmed canertinib-induced ototoxicity in two distinct mouse models.
- Provided evidence for an evolutionarily conserved ERBB-mediated mechanism of canertinib ototoxicity.
Conclusions:
- Canertinib exhibits significant ototoxicity, likely via an evolutionarily preserved ERBB pathway.
- Clinical monitoring for hearing loss is recommended during canertinib and other pan-ERBB inhibitor trials.
- Highlights the importance of evaluating drug-induced ototoxicity in preclinical models.
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