Cisplatin-Associated Hearing Loss Is More Severe in Patients With Cockayne Syndrome

Although cisplatin can kill cancer, the chemotherapy agent can also cause permanent hearing loss. The drug kills sensory cells of the inner ear, and the effects on the inner ear are likely more severe in persons with the rare form of dwarfism known as Cockayne syndrome.1

Cockayne syndrome results from mutations in 1 of the 2 genes Csa and Csb, which are involved in repairing DNA damage.

"Chemotherapy using the drug cisplatin saves lives by killing rapidly dividing cancer cells, so it is a mystery why a major side effect of treatment is hearing loss caused by the death of the nondividing sensory hair cells of the inner ear," said Neil Segil, PhD, a professor of research in the Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of the University of Southern California (USC), and senior author of the study.

"Our studies of a mouse model of Cockayne syndrome are the first to point to the importance of ongoing DNA repair in protecting the sensitive sensory hair cells of the inner ear from such environmental stress. We show that the same mutations, causing Cockayne syndrome in humans, make the sensory hair cells of mice hypersensitive to DNA damage caused by cisplatin chemotherapy."

Humans with Cockayne syndrome can experience hearing loss, eye abnormalities, shortness, skeletal deformities, microcephaly, nervous system underdevelopment, an appearance of premature aging, and sun sensitivity.

Cisplatin damages the DNA in cells, which interferes with their ability to proliferate. This interference is expected to have its most pronounced effects on cells that proliferate the most, such as cancer cells, and less effect on cells that are nondividing, such as the sensory cells of the inner ear. In practice, however, cisplatin causes significant death rates for both quickly dividing cancer cells and for the nondividing cells of the inner ear. So, cisplatin is an effective chemotherapy that commonly causes severe hearing loss. Young children who are treated with cisplatin chemotherapy are particularly vulnerable to hearing loss and early hearing loss leads to development delays.

This study examined mice with mutations in Csa and Csb, so they also could not efficiently repair DNA damage and were particularly vulnerable to permanent hearing loss from cisplatin.

"Our cells have several biochemical pathways that they use to repair DNA," Segil said. "Our findings suggest that one particular pathway, transcription-coupled DNA repair, is a major force for protecting the cells of the inner ear from cisplatin. The impairment of this repair pathway in patients with Cockayne syndrome leaves them particularly vulnerable to severe hearing loss as a side effect of taking this chemotherapy drug."


1. Rainey RN, Ng SY, Llamas J, et al. Mutations in Cockayne syndrome-associated genes (Csa and Csb) predispose to cisplatin-induced hearing loss in mice. J Neuroscience. 2016;36(17):4758. doi:10.1523/JNEUROSCI.3890-15.2016.

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