Heat Shock Protein (Hsp) 90 Inhibitor-Induced Ocular Toxicity: Critical Role of Tissue Distribution

Background: In addition to regulating oncogenic client proteins, the Hsp90 molecular chaperone also controls the folding of key signaling molecules required to maintain normal cell function in many organs, including the retina. In human clinical trials a number of Hsp90 inhibitors have been associated with visual disorders including blurred vision, flashes, delayed light/dark accommodation, and photophobia. These adverse effects involving injury to the retina may be attributable to photoreceptor degeneration and cell death, as previously reported in dogs following repeated doses of Hsp90 inhibitor PF-04929113 . In contrast, ganetespib, a potent Hsp90 inhibitor currently in phase II/III trials, has demonstrated promising clinical activity without manifesting ocular toxicity.