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

Canertinib induces ototoxicity in three preclinical models

Hear Res. 2015 Oct:328:59-66. doi: 10.1016/j.heares.2015.07.002. Epub 2015 Jul 7.

Authors

Jian Tang¹, Yi Qian², Hui Li³, Benjamin J Kopecky⁴, Dalian Ding⁵, Henry C Ou⁶, Rhonda DeCook⁷, Xiaojie Chen⁸, Zhenyu Sun², Megan Kobel⁹, Jianxin Bao¹⁰

Affiliations

¹ 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.
² Department of Cardio-Thoracic Surgery, The Third Affiliated Hospital of Nantong University, Wuxi 214041, China.
³ 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.
⁴ Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵ Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA.
⁶ Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA; Department of Otolaryngology, University of Washington, Seattle, WA, USA.
⁷ Department of Statistics and Actuarial Science, University of Iowa, Iowa City, IA 52242, USA.
⁸ Gateway Biotechnology Inc., St. Louis, MO 63108, USA.
⁹ Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
¹⁰ 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.

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.

Keywords: Canertinib; ERBB; NRG1; Non-small cell lung cancer; Ototoxicity; Outer hair cell.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

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

Substances

Antineoplastic Agents
Morpholines
Neuregulin-1
Nrg1 protein, mouse
Canertinib
ErbB Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding