Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs

Abstract

-Heat shock protein 90 (Hsp90) is a constitutively expressed molecular chaperone and plays an important role in the folding of client proteins with key regulatory roles in growth, survival, differentiation and metastasis. Because inhibition of Hsp90 degrades multiple oncogenic client proteins, it is considered to be an attractive anticancer therapy, and clinical trials of several Hsp90 inhibitors have been carried out. In the present study, two structurally distinct Hsp90 inhibitors, CH5164840 and CH5449302, were orally administered to beagle dogs to evaluate systemic toxicity. CH5164840 induced symptoms that suggest visual disorder, and ophthalmological observation and electroretinography (ERG) revealed loss of pupillary light reflex and abnormal waveforms, respectively. Histopathological examination showed changes in the photoreceptor cell layer and the outer nuclear layer of retina. On the other hand, while there were no clinical symptoms related to visual disorder, animals treated with CH5449302 showed similar abnormalities of ERG responses and histopathological changes in the photoreceptor cell layer and the outer nuclear layer of retina. The visual symptoms and abnormalities of ERG responses were noted at an earlier stage or lower dose than other toxicities in both compounds. Considering that two structurally distinct Hsp90 inhibitors induced a retinal toxicity in dogs after repeated administration, and that visual disorders were also reported in some clinical trials of Hsp90 inhibitors, it would seem highly likely that Hsp90 inhibition induces retinal toxicity. Also, our study indicated that a detailed ocular examination to evaluate the safety of Hsp90 inhibitors would be useful in both preclinical and clinical studies.

First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors

“…HSP90 plays a critical role also in retinal function, and sustained HSP90 inhibition may be associated with eye disorders (19)(20)(21). Effects of TAS-116 on retina have yet to been examined; it was reported that reduction of rhodopsin kinase (GRK1), one of HSP90 client proteins, by sustained HSP90 inhibition adversely affects visual function (22).…”

Chaperome heterogeneity and its implications for cancer study and treatment

“…To target the epichaperome in clinic, inhibitors that discriminate between a single chaperome and a chaperome incorporated into epichaperomes (that is HSP90 versus HSP90-containing epichaperomes for example) are preferred for treatment as they may offer better target engagement and a safer profile (22,46). Although acute chaperome inhibition may not be toxic to normal cells, chronic suppression may have unwanted effects (107,108). A number of review articles have been written on the discovery, identity, and mode of action of small molecule inhibitors of HSP90, HSP70, and others (62, 109 -117), and the reader is referred to these sources for further expansion on this topic.…”

Synthesis and Evaluation of a Novel Deguelin Derivative, L80, which Disrupts ATP Binding to the C-terminal Domain of Heat Shock Protein 90

“…A previous study reported a Parkinson's disease-like syndrome in rats treated with deguelin at high doses (Caboni et al, 2004). In addition, it was reported that Hsp90 inhibitors may induce ocular toxicity (Kanamaru et al, 2014). Although it is not clear whether therapeutic doses of deguelin would induce the side effects and whether the side effects can be relieved after drug withdrawal, the potential toxicities of deguelin can be a considerable obstacle to its clinical use.…”