Abstract 2094: Hsp70 inhibitors overcome tamoxifen resistance, in cell culture model

Abstract A prevalent problem in the use of chemotherapies for the treatment of human cancers is the potential for the development of resistance. While the exact nature of the mechanisms involved in resistance development vary based on cancer type as well as the nature of the therapeutics; some oncogenic factors have been established to have roles in the desensitization to common treatments. Previous data from our lab demonstrated Hsp70 inhibitors can reduce Akt levels. a major proliferation and survival factor also linked to estrogen receptor therapeutic based resistance. We have, Uusing these Hsp70 ATPase-inhibiting compounds and ain a cell culture model of tamoxifen resistant breast cancer, we have identified compounds which can re-sensitize resistant cells. These compounds inhibit cytosolic and mitochondrial members of the 70-kDA heat-shock protein family. These compounds also reduce Akt levels, a major proliferation and survival factor also linked to estrogen receptor therapeutic based resistance, as well as Thus, in addition to reducing Akt levels and possibly other oncogenic chaperone clients, these drugs may also interrupt mitochondrial function leading to reduced viability in the presence of tamoxifen. With these mechanisms in mind, we now have data that Ttamoxifen resistant MCF7 cells regained sensitivity to tamoxifen after brief treatments with Hsp70-family inhibitors. The resistant cells were grown in media containing tamoxifen. This media was replaced with media containing an Hsp70 inhibitor compound for four hours. After the four hours, the Hsp70 inhibitor media was removed and tamoxifen-containing media was reapplied to the cells. Multiple viability and cytotoxicity assays confirm the drop in viability and increased cytotoxicity following these treatments. These studies demonstrate that Hsp70 family members are potentially valuable targets for new cancer therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2094. doi:10.1158/1538-7445.AM2011-2094