Abstract Introduction: DLBCL is a fast-growing, aggressive form of NHL and ~30% of the patients are not cured with the current treatment regimens. Recently Wnt/ ß-catenin signaling has been identified as a new target pathway for lymphoma. To specifically target B-catenin we picked two drugs that act downstream of the Wnt/B-catenin pathway. ICG-001 inhibits TCF/β-catenin mediated transcription by competing specifically with β-catenin for CREB binding protein (CBP), but not for p300. PAM-1 is a p21-activated kinase 4 (PAK4) allosteric modulator acting as a nucleo-cytoplasmic shuttling protein. PAK4 interacts with and phosphorylates β-catenin on Ser675, promoting TCF/B-catenin transcriptional activity and stabilizing β-catenin through inhibition of its degradation. We conducted a pre-clinical study with ICG-001 and PAM-1 ß-catenin inhibitors on 16 ABC and GCB DLBCL cell lines and provided a molecular rationale for Wnt/ß-catenin directed therapy. Material & Methods: RNAseq data from DLBCL cell lines, patient and normal B-cell samples were used to profile transcript abundance of the Wnt pathway in DLBCL. Western blotting was used to measure ß-catenin expression in 16 ABC and GCB DLBCL cell lines. Pharmacological inhibition of ß-catenin-signaling was tested using ICG-001 and PAM-1 compounds. A metabolically active cellular assay (CellTiter Glo) and flow cytometry with annexin V staining were used to determine cell viability and apoptosis. To address the specificity of the drug response, DLBCL cells were transduced with a ß-catenin/TCF pathway reporter, knocked down for ß-catenin, and canonical Wnt target expression was assessed using quantitative real-time (qRT-PCR) and Western blot. Results: ß-catenin is expressed on all DLBCL cell lines at different levels that do not correlate with the ABC/GCB classification. The ß-catenin inhibitors ICG-001 and PAM-1 significantly reduced viability in all ABC and GCB DLBCL cell lines, regardless of DLBCL subtype. The EC50 after 48h of treatment ranged from 1.4 μM to 6.3 μM for ICG001 and from 80 nM to 870 nM for PAM-1. Both compounds suppressed cell proliferation, induced apoptosis, and reduced Wnt/ß-catenin transcriptional activity. Conclusions: Our data indicate that targeting ß-catenin pathway with ICG-001 and PAM-1 could be therapeutically beneficial to DLBCL patients. Disclosures Melnick: Janssen: Research Funding.