Canertinib induces ototoxicity in three preclinical models

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.