LAUSR

(5) RNA-seq. The abundance of gene transcriptswas determined by RNA sequencing, using the Illumina HiSeq 2500 platform. (6) Proteomic studies were performed using data independent analysis (DIA) Liquid chromatography–mass spectrometry (LC/MS). (7) Data analysis. Omics data were analyzed by gene set enrichment analysis (GSEA) and Virtual Inference of Protein-activity by Enriched Regulon (VIPER) analysis. Results: Umbralisib and carfilzomib in combination, but not the single agents, inhibited phosphorylation of 4E-BP1 in DLBCL and MCL cells. The combination potently inhibited assembly of eIF4F, inhibited polysomes, and selectively downregulated target genes in the following signatures: c-Myc, E2F, G2M checkpoint, and DNA repair. More than 5,000 proteins were detected by LC/MS, and about 400 proteins were significantly decreased. The proteins downregulated were enriched with transcription factors and proteins involved in chromosome/DNA modification. These results suggest that umbralisib and carfilzomib synergistically inhibit cap dependent translation of tumor promoting genes, and represent a promising treatment for lymphoma.