Abstract 4734: Genes cooperatively downregulated by combined mTOR/histone deactylase (HDAC) inhibition are overexpressed in myeloma patients with lower survival

Abstract The molecular pathogenesis of many cancer types, including multiple myeloma (MM) and mantle cell lymphoma (MCL), involves alterations in the PI3K/Akt/mTOR and cyclin/CDK/CDKI/Rb (Rb) pathways. Previously, we showed that the combination of an HDAC inhibitor (HDACi) with rapamycin synergistically inhibited proliferation in 88% of human MM cell lines tested, and effectively controlled tumor growth in preclinical studies. To gain an initial understanding of the molecular mechanism of the synergistic action of the drug combination, we used an unbiased systems-level approach to analyze our gene expression profile (GEP) data with weighted gene co-expression network analysis (WGCNA). This analysis delineated the contribution of HDACi and rapamycin, singly and in combination, to the overall gene expression change of the combination by considering not only measures of fold-change and significance testing, but also the degree of gene expression inter-connectedness. WGCNA identified five gene modules, each representing a particular gene expression effect of the combination. Each gene module was individually tested for functional and clinical enrichment using gene set enrichment analysis (GSEA) and survival analyses with Cox regression. Of particular interest, the module containing genes cooperatively affected by both compounds was highly enriched (p<0.001) for genes involved in cell cycle (especially mitotic processes), immune recognition, and DNA damage/repair, which we investigated further. Genes down-regulated by the drug combination were most significantly correlated with genes over-expressed in MM patients. Furthermore, analysis of the cooperative drug signature in publicly available patient GEP datasets with survival annotation found it predictive of increased survival (p<0.01), thus linking the drug combination-induced transcriptional changes to predictions for enhanced survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4734. doi:1538-7445.AM2012-473