Heat shock protein 90 (HSP90) has been shown to be overexpressed in a wide range of cancers, and plays a critical role in tumor cell growth and survival by stabilizing aberrant signaling proteins and by interfering with apoptosis. Several natural and synthetic inhibitors of HSP90 have been shown to have antitumor effects, but single agent development has been limited by poor solubility, poor availability and off-target toxicities (hepatotoxicity, retinal toxicity). The aim of this study is to investigate the biological activity of the small-molecule HSP90 inhibitor, AT13387 (Astex Pharmaceuticals) for antitumor activity in head and neck squamous cell carcinoma (HNSCC). Human HNSCC cell lines, UMSCC −1 (wild-type p53) and −46 (mutant p53) were treated with AT13387. The inhibitory concentrations (IC[[Unsupported Character - Codename ­]]50) of AT13387 on HNSCC cell lines were determined using MTT proliferation assay. AT13387 (55 mg/kg two consecutive days every week) antitumor activity, toxicity and survival were evaluated in the UMSCC −1 and −46 xenograft model in BALB/c SCID mice. AT13387 inhibited the proliferation of both UMSCC cell lines in vitro with IC50 levels of 0.05-.10 µM by MTT assay. In vivo, AT13387, at 55 mg/kg showed significant antitumor effect and improved survival in both wtTP53 UMSCC-1 and mtTP53 UMSCC-46 xenograft models. The treatment was well-tolerated and no significant body weight loss observed. These data suggest that AT13387 may possess potent antitumor activity in human HNSCC, regardless of the p53 mutation status. The potential of AT13387 as a chemosensitizer for radiotherapy is being investigated. These preclinical data suggest that AT13387 holds promise as a potential chemotherapeutic agent for HNSCC clinical trials. (Supported by NIDCD project ZIA-DC-000073 and AT13387 provided to NCI by Astex Pharmaceuticals)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2770. doi:1538-7445.AM2012-2770