Canertinib induces ototoxicity in three preclinical models.

Canertinib induces ototoxicity in three preclinical models.

Tang Jian; Qian Yi; Li Hui; Kopecky Benjamin J; Ding Dalian; Ou Henry C; DeCook Rhonda; Chen Xiaojie; Sun Zhenyu; Kobel Megan; Bao Jianxin

Hearing research

2015

2015-10

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.

Animals; Antineoplastic Agents/*adverse effects/pharmacology; Antitumor; Auditory; Canertinib; Carcinoma; Drug Screening Assays; Ear; Electrophysiology; ERBB; ErbB Receptors/*antagonists & inhibitors; Female; Hair Cells; Hearing Loss/*chemically induced; Hearing/*drug effects; Inbred C57BL; Inbred CBA; Lung Neoplasms/drug therapy; Male; Mice; Morpholines/*adverse effects/pharmacology; Neuregulin-1/metabolism; Non-small cell lung cancer; Non-Small-Cell Lung/drug therapy; NRG1; Ototoxicity; Outer hair cell; Outer/*drug effects; Signal Transduction/drug effects; Zebrafish

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

59–66

328