Abstract 7598: The novel eIF4A inhibitor potently synergizes with BCL2 inhibitor in high grade B-cell lymphoma with MYC and BCL2 rearrangements through regulating UPR
Authors: Seol So-Young , Park Chung Hyun , Kim Soo Jeong , Chung Haerim , Cho Hyunsoo , Kim Jin Seok , Kim Yu Ri 
Published: March 2024

Abstract
Double hit lymphoma(DHL) is defined to be a chromosomal break with MYC gene combined with BCL2 or BCL6. MYC is an oncogene which proliferation the cells and BCL2 inhibit cell death. These combinations could be a cause of highly aggressive clinical features and poor survival of DLBCL. The WHO-HAEM5 renames the entity DLBCL/high-grade B-cell lymphoma with MYC and BCL2 rearrangements. Despite the dismal prognosis, no widely accepted standard treatment exists to the management of DHL. Therefore, new therapeutic approaches for these patients are urgently needed. Previously, we looked at the eIf4A inhibition was shown to downregulate MYC expression in lymphoma cell lines. Venetoclax, a highly selective inhibitor of BCL2, shows clinical activity for patients with DLBCL although there are concerns about increasing toxicity. Our hypothesis in the following: If eIF4A inhibitor preferentially inhibit the translation of oncogenes such as cMyc and venetoclax inhibit the BCL2 in DHL, then the combination of eIF4A inhibitor and BCL2 inhibitor will be highly effective for DHL and potentially safe for animals and humans. We tested the anti-lymphoma effect of CR-1-31-B, in combination with Venetoclax in lymphoma cell lines using flow cytometry. We performed cell apoptosis assays in increasing concentrations of Venetoclax, CR-1-31-B and a combination of the two drugs at 48 hours. To better understand molecular mechanisms underlying the observed synergistic effect in DLBCL-DHL, RNA-seq profiling was performed on cells treated with single drugs and their combinations, respectively. Venetoclax and CR1-31-B exhibited concentration and time dependent cytotoxicity in lymphoma cell lines at low nanomolar concentrations. Overall, the combination of eIF4A inhibitor and BCL2 inhibitor showed synergy in all kinds of DLBCL cell lines. Especially DHL cell lines were more sensitive to the drug combination and showed enhanced synergy compared to the non-DHL cell lines(p&lt;0.0001). We analyzed RNA-seq profiling of cells treated with single drugs and their combinations and found that the transcriptional signature of the synergistic combination was unique relative to that of either constituent monotherapy. Gene set enrichment analysis was performed in the DHL and non-DHL group. The analysis demonstrates that known Unfolded protein response(UPR) part and metabolism, are enriched in DHL groups. This suggests that the UPR and metabolism pathway are closely related to the combination effect in DHL. These findings suggest that the combination of eIF4A inhibitor and BCL2 inhibitor have potent pharmacological activity in DHL lines, it was closely related with UPR. These combination is promising and novel treatment for high-grade B-cell lymphoma with MYC and BCL2 rearrangements. Further pre-clinical investigations of this combination for these patients are needed.
Citation Format: So-Young Seol, Chung Hyun Park, Soo Jeong Kim, Haerim Chung, Hyunsoo Cho, Jin Seok Kim, Yu Ri Kim. The novel eIF4A inhibitor potently synergizes with BCL2 inhibitor in high grade B-cell lymphoma with MYC and BCL2 rearrangements through regulating UPR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7598.