A2A or Beta-2 Adrenergic Receptor Agonist Synergies Induce Distinct Patterns of Gene Expression Relevant to Multiple Myeloma Cell Survival.

Abstract 3831 Poster Board III-767 Using a high-throughput combination screening strategy, we have demonstrated that adenosine A2A receptors (A2AR) or beta-2 adrenergic receptors (bAR) agonists, in low nano-molar range, exhibit highly synergistic anti-proliferative activity when combined with Multiple Myeloma drugs, such as dexamethasone, lenalidomide, bortezomib, melphalan and doxorubicin at clinically relevant concentrations. Synergy and selectivity have been observed in multiple myeloma (MM) cell lines and ex vivo using patient tumor cells. To understand this synergistic mechanism, we employed the Affymetrix U133 plus 2.0 cDNA microarray to investigate the differentially expressed genes in a multiple myeloma MM1.S cell line treated with A2AR agonists, bAR agonists, dexamethasone, or in combinations (A2AR/ bAR agonists and dex) for six hours. Using conventional hierarchical clustering, unsupervised analyses clearly separate the A2AR/ bAR agonists or the dexamethosone groups from the combination groups, suggesting a unique mechanism underlying the combination treatments. With SAM (Significance Analysis of Microarrays), we found 314 and 309 genes that showed statistically significant up-regulation or down-regulation respectively in the combination groups compared to the untreated control, with a false discovery rate= Disclosures: Tam:CombinatoRx, Inc.: Employment. Rickles:CombinatoRx, Inc.: Employment. Giordano:CombinatoRx, Inc.: Employment. Borisy:CombinatoRx, Inc.: Employment. Lee:CombinatoRx, Inc.: Employment.