Canertinib induces ototoxicity in three preclinical models

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

doi:10.1016/j.heares.2015.07.002

Back

Canertinib induces ototoxicity in three preclinical models

Journal article

Peer reviewed

Canertinib induces ototoxicity in three preclinical models

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

Hearing research, Vol.328, pp.59-66

10/2015

DOI: 10.1016/j.heares.2015.07.002

PMCID: PMC4581429

PMID: 26163095

View Online

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. •Canertinib, a new cancer drug candidate blocking ERBB signaling, causes toxicity in hair cells of zebrafish lateral line.•Canertinib ototoxicity is confirmed in two mouse models.•One major target of its ototoxicity in mice is outer hair cells.•Ototoxicity should be monitored for cancer drug candidates with pan-ERBB inhibition properties.

NRG1

Canertinib

ERBB

Outer hair cell

Non-small cell lung cancer

Ototoxicity

Details

Title: Subtitle: Canertinib induces ototoxicity in three preclinical models
Creators: Jian Tang - Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA
Yi Qian - Department of Cardio-Thoracic Surgery, The Third Affiliated Hospital of Nantong University, Wuxi 214041, China
Hui Li - Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA
Benjamin J Kopecky - Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA
Dalian Ding - Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA
Henry C Ou - Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA
Rhonda DeCook - Department of Statistics and Actuarial Science, University of Iowa, Iowa City, IA 52242, USA
Xiaojie Chen - Gateway Biotechnology Inc., St. Louis, MO 63108, USA
Zhenyu Sun - Department of Cardio-Thoracic Surgery, The Third Affiliated Hospital of Nantong University, Wuxi 214041, China
Megan Kobel - Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, OH 44272, USA
Jianxin Bao - Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA
Resource Type: Journal article
Publication Details: Hearing research, Vol.328, pp.59-66
DOI: 10.1016/j.heares.2015.07.002
PMID: 26163095
PMCID: PMC4581429
NLM abbreviation: Hear Res
ISSN: 0378-5955
eISSN: 1878-5891
Publisher: Elsevier B.V
Grant note: name: National Institute of Health, award: DC010489, DC011793
Language: English
Date published: 10/2015
Academic Unit: Statistics and Actuarial Science
Record Identifier: 9983985884002771

Metrics

29 Record Views

9 Times Cited - Web of Science

See more details