Journal
HEARING RESEARCH
Volume 328, Issue -, Pages 59-66Publisher
ELSEVIER
DOI: 10.1016/j.heares.2015.07.002
Keywords
Ototoxicity; Outer hair cell; Non-small cell lung cancer; ERBB; NRG1; Canertinib
Funding
- National Institute of Health [DC010489, DC011793]
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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. (C) 2015 Elsevier B.V. All rights reserved.
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