Targeting of PIM Kinases Shows Single Agent Efficacy and Synergizes With BCL2 Inhibitors in Diffuse Large B Cell Lymphoma of the ABC Subtype

Abstract

The PIM family of serine/threonine kinases (PIM1, PIM2, and PIM3) are involved in the development of cancer and represent promising therapeutic targets. We investigated the therapeutic potential of targeting PIM kinases in diffuse large B-cell lymphoma (DLBCL), particularly the activated B-cell-like (ABC) subtype, using the pan-PIM inhibitor AZD1208. We demonstrated that PIM1 and PIM2 are more highly expressed in ABC- cells than in germinal center B-cell-like (GCB) -DLBCL cells, and that ABC-DLBCL cell lines are more sensitive to PIM inhibition with AZD1208. Transcriptome analysis of ABC-DLBCL cell lines treated with AZD1208 revealed a downregulation of genes involved in NF-κB signaling, a crucial pathway for ABC-DLBCL. We also explored synergistic drug combinations using a high-throughput screen, which identified BCL2 and glutaminase inhibitors as effective partners for AZD1208, particularly in aggressive ABC-DLBCL and double-hit cell lines. The combination of AZD1208 with the clinically available BCL2 inhibitor venetoclax was synergistic in most DLBCL cell lines, and this combination induced apoptosis and reduced levels of AKT and MCL1 proteins. In conclusion, our findings suggested that AZD1208, especially when combined with BCL2 inhibitors like venetoclax, holds promise as a treatment strategy for aggressive lymphomas. These combinations may enable lower doses of PIM inhibitors, leading to increased tolerability and improved anti-tumor activity in clinical settings. The study also highlighted the potential for targeting PIM kinases in combination with other therapies to overcome drug resistance in DLBCL.