Abstract 2634: Combination of HSP90 and mTOR inhibition promotes pancreatic cancer growth inhibition

Abstract

Abstract The molecular determinants of resistance to mTOR targeted therapies remain unspecified. Genomic analysis has demonstrated that a number of gene families promoting intracellular signal transduction are overexpressed in mTOR resistant human pancreas explant xenografts. Heat shock proteins serve as molecular chaperone for many of the proteins implicated in the analysis. As such, it was hypothesized that proximal intracellular signal transduction inhibition with a HSP90 inhibitor could overcome inherent pancreas cancer resistance to mTOR inhibitors. Fourteen human pancreatic cell lines have been analyzed with respect to their proliferative capacity upon exposure to RAD001 (mTOR inhibitor) and AUY922 (HSP90 inhibitor), both as single agents and in combination. In vitro analysis with CalcuSyn® software demonstrates synergistic antiproliferative effects of these two drugs. For example, combination index (CI) values ranging from 0.01 to 0.5 were observed when the mTOR resistant cell line PANC02.03 was treated with the combination of RAD001 and AUY922. In vivo treatment of the L3.6 xenograft model with AUY922 and RAD001 resulted in preferential tumor growth inhibition of the combination relative to either drug alone. These effects were associated with the inhibition of the pI3K/AKT/mTOR and the ERK pathways. In summary, proximal signal transduction inhibition by a HSP90 may overcome inherent pancreas cancer mTOR inhibitor resistance. Future work is designed to extend these finding and to determine the specific pathways that are necessary for the observed growth inhibition. 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 2634.