Abstract P4-02-13: Heat Shock Protein 90 Inhibitors: New Targeted Therapy To Overcome Aromatase Inhibitor Resistance

Abstract

Abstract CA Aromatase inhibitors (AIs) are important drugs to treat ERα + postmenopausal breast cancer patients. Although AIs are highly effective drugs, unfortunately, a significant number of AI-treated patients will develop disease progression due to resistance. There are two types of AI resistance: de novo/intrinsic resistance and acquired resistance. In order to study the mechanisms of endocrine resistance and to explore ways to prevent/delay and treat endocrine resistance, our laboratory prepared a set of resistant cell lines with the consideration of physiological relevance of the models. We have two de novo resistant cell lines (MCF7Akt-aro and MCF7HER2-aro). These lines have functionally active aromatase and ER that can be inhibited by AIs and antiestrogens, respectively. However, these drugs cannot suppress the proliferation of the cells because their proliferation is driven predominantly by activated Akt or HER2. MCF7aro was generated by over-expressing aromatase in MCF7 cells and used to study response to AIs. A series of MCF7aro cell lines that acquired resistance to each of three AIs (letrozole, anastrozole, exemestane) or tamoxifen were then generated. These MCF7aro-derived cell lines have been extensively characterized and verified to be relevant models of acquired endocrine resistance. Furthermore, long-term estrogen deprived MCF7aro lines (LTEDaro) were generated and shown to represent a model of late stage acquired resistance that does not respond to treatment of any AI or tamoxifen. Affected by tumor microenvironment, it is not unexpected that multiple signaling pathways are up-regulated in endocrine resistant tumors. Therefore, inhibitors that target a single pathway will be only effective for some, but not all, endocrine resistant patients. Furthermore, secondary resistance may occur following the treatment with a highly selective drug. Recognizing such possible outcomes, we feel that effective treatment of endocrine resistance could result from the use of drugs with multiple targets. Heat shock protein 90 (HSP90) is a chaperone protein that functions to assist other proteins, termed “client proteins,” in their proper folding. Many HSP90 client proteins include those involved in cell proliferation and survival. Therefore, they were thought to be useful against AI resistance due to their capability of targeting multiple proteins simultaneously. We examined the effect of 17-(dimethylaminoethylamino)- 17-demethoxygeldanamycin (17DMAG), a HSP90 inhibitor, on our hormone-responsive and -resistant cell lines. Our experiments reveal that proliferation of hormone-responsive MCF7aro cells can be suppressed by 17DMAG and letrozole in a synergistic manner. Furthermore, 17DMAG was found to be very effective in suppressing the proliferation of both de novo and acquired endocrine resistant cells, but the treatment cannot re-sensitize the cells to letrozole. 17DMAG induced apoptosis and G2 cell cycle arrest in both cell lines. Moreover, mechanistic studies revealed decreased HER2, Akt, cyclin D1, and Bcl2 protein expression with 17DMAG treatment. Collectively, our results support that endocrine resistance can be delayed or prevented by a combined use of HSP90 inhibitors and AIs, and HSP90 inhibitors will be useful in overcoming endocrine resistance. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-13.