Genomic and Pathway Connectivity Analyses Identify Novel Strategies to Overcome mTOR Inhibitor Resistance In DLBCL

Abstract 436 mTOR inhibitors have been used with clinical success in solid tumors and non-Hodgkin lymphoma (NHL), and are attractive therapeutic options for DLBCL (diffuse large B-cell lymphoma, which has been shown to have constitutively active mTOR signaling). However, resistance to this class of agents remains problematic, and mechanisms of resistance are poorly understood. We performed candidate drug discovery using connectivity mapping and global gene expression profiling (GEP) to understand the pathways and genes responsible for resistance to the mTOR inhibitor Rapamycin (Sirolimus), which is the active metabolite of several clinically available mTOR inhibitors (eg, Temsirolimus, Everolimus). Treatment of DLBCL cell lines by Rapamycin at varying doses permitted stratification of cell lines into 2 groups of 3 cell lines each: sensitive (SU-DHL6, WSU-NHL, and Karpas-422) and resistant (SU-DHL4, OCI-Ly19, and Farage). Using the Affymetrix Human Gene 1.0 ST Array, we generated a profile of 1164 differentially-expressed genes (P Disclosures: No relevant conflicts of interest to declare.