title: Canertinib induces ototoxicity in three preclinical models.
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.
authors.affiliation: Department 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Cardio-Thoracic Surgery, The Third Affiliated Hospital of Nantong University, Wuxi 214041, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Kopecky
authors.affiliation: Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA.
authors.forename: Dalian
authors.initials: D
authors.lastname: Ding
authors.affiliation: Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA; Department of Otolaryngology, University of Washington, Seattle, WA, USA.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Ou
authors.affiliation: Department of Statistics and Actuarial Science, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: DeCook
authors.affiliation: Gateway Biotechnology Inc., St. Louis, MO 63108, USA.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cardio-Thoracic Surgery, The Third Affiliated Hospital of Nantong University, Wuxi 214041, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Kobel
authors.affiliation: Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, OH 44272, USA. Electronic address: jbao@neomed.edu.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Bao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D004423:Ear; D004594:Electrophysiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects*; D006309:Hearing / Q000187:drug effects*; D034381:Hearing Loss / Q000139:chemically induced*; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009025:Morpholines / Q000009:adverse effects* / Q000494:pharmacology; D020890:Neuregulin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; C420268:Canertinib; D066246:ErbB Receptors
keywords: Canertinib; ERBB; NRG1; Non-small cell lung cancer; Ototoxicity; Outer hair cell