Transcriptomic analysis of lenalidomide and ENMD-2076 combination drug treatment in a human plasmacytoma xenograft mouse model.

e19565 Background: ENMD-2076 is a novel oral multi target kinase inhibitor with specific activity against aurora kinases. We have previously demonstrated an additive/synergistic effect of ENMD-2076 and Lenalidomide(LLMD) against myeloma cell lines in a murine model. The purpose of this study was to investigate differential gene expression following combination drug treatment with ENMD-2076 and LLMD in comparison to single drug regimen. Methods: Gene expression analysis by microarray was performed on human plasmacytoma cells obtained from xenografted H929 cells following treatment with ENMD-2076 in combination with LLMD compared to single drug regimen. Ingenuity Pathway Analysis (IPA) was performed to identify the pathways affected by these genes. Results: While treatment with ENMD-2076 alone did not produce significant changes in gene expression, 868 genes were differentially expressed following treatment with LLMD, and 2004 genes were differentially expressed when ENMD-2076 and LLMD were used in combination (FDR ≤1%). The IPA revealed that genes being differentially expressed were integral to various signaling pathways, such as PI3K/AKT, mTOR, ATM, ERK/MAPK, GADD45, cdc42, p53, JAK/STAT, and VEGF. Treatment with the combination regimen affected a significantly higher ratio of molecules in these pathways than with LLMD alone. Conclusions: ENMD-2076 with LLMD synergistically alter expression of several key genes in canonical pathways regulating cell cycle, proliferation, apoptosis and cell signaling.