Abstract 606: Heat shock protein 90 inhibitors: New mode of therapy to overcome aromatase inhibitor resistance

Abstract

Abstract Results from several major trials have revealed that aromatase inhibitors (AIs) are superior to tamoxifen with regard to disease progression, incidences of locoregional and distant relapses, and contralateral breast cancers. Although AIs are highly effective drugs (with outstanding specificity and potency), unfortunately, a significant number of AI-treated breast cancer patients will eventually develop disease progression due to acquired resistance. Hormone refractory breast cancers result from complex molecular changes and are challenging to cure. Recently, we examined whether the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) can inhibit the growth of AI-resistant breast cancers and the mechanisms by which 17-DMAG affects proliferation. AI-responsive MCF-7aro and AI-resistant LTEDaro breast epithelial cells were used in this study. We observed that 17-DMAG inhibited proliferation in both MCF-7aro and LTEDaro cells in a dose-dependent manner. 17-DMAG induced apoptosis and G2 cell cycle arrest in both cell lines. Although inhibition of HSP90 decreased the levels of ERα, the ERα transcriptional activity was not affected when cells were treated with 17-DMAG together with estradiol. Moreover, detailed mechanistic studies suggested that 17-DMAG inhibits cell growth via degradation of HSP90 client proteins AKT and HER2. Furthermore, our experiments using AI responsive MCF-7aro cells have revealed that HSP90 inhibitors such as 17-DMAG and AIs such as letrozole can suppress the proliferation of hormone-dependent breast cancer cells in a synergistic manner. To study de novo AI-resistance, our lab has generated MCF-7 cell models to overexpress both aromatase and either Akt (MCF-7Aktaro) or HER2 (MCF-7aroHER2). We have found that HSP90 inhibitor 17-DMAG is also effective on suppressing the proliferation of these de novo AI resistant cells. Collectively, results from this study provide data to support the theory that HSP90 inhibitors may be an effective therapy to delay and treat AI-resistant breast cancers (This research was supported by the NIH grant CA44735). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 606.