Identification of the correlation between drug activity and sensitivity of HSP90 inhibitors in breast cancer cells using a multivariate gene expression assay

Abstract

22214 Background: Heat shock protein 90 (HSP90) is a ubiquitously expressed molecular chaperon which has become a well defined drug target for a variety types of cancer. In a previous study, we had developed a 31-gene, multivariate gene expression assay to monitor multiple pathways of pharmacodynamic activity of HSP90 inhibitors in cancer cells. This study evaluated the dose and time-dependent expression responses but did not explore compound specificity (AACR 2007). We have broadened these studies to elucidate the differential activities of a pair of chemically different HSP90 inhibitors in multiple cell lines. Methods: To understand the relationship between the expression profiles and drug sensitivities, the gene expression levels for the 31 genes were measured following the treatment of two HSP90 inhibitors, 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) and Ridicicol. Using our multivariate assay their GI50s were measured in 4 human breast cancer cell lines, 2 HSP90 sensitive and 2 HSP90 insensitive. Unsupervised clustering analysis was performed to assess the relationships between compound activities and their sensitivities in these cancer cells. Results: We have observed that the cancer cells showed different expression profiles based upon the HSP90 inhibitor treatment and the cell line used. In addition, the clustering results on the expression profiles of untreated cells clearly separate sensitive from insensitive breast cancer cell lines. Conclusions: Our multivariate gene expression assay for the HSP90 inhibitors shows strong correlation between drug activity and drug sensitivity in cancer cells. This assay also showed potential to be used as a stratification biomarker to identify breast tumors that might respond well to HSP90 inhibitors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Althea Technologies Inc.