PIM kinase inhibitor, AZD1208, inhibits protein translation and induces autophagy in primary chronic lymphocytic leukemia cells

Abstract
The serine/threonine kinases PIM1, PIM2, and PIM3 are important for the growth and survival of cancer cells. Mice lacking these kinases are viable, indicating that they are potential therapeutic targets, especially since these proteins are overexpressed in various human hematological cancers. Several small molecule inhibitors have been developed to target these kinases. Notably, AZD1208 is an orally administered small-molecule drug that effectively inhibits all three PIM kinases at low nanomolar concentrations. It has been evaluated in clinical trials for patients with solid tumors and hematological cancers, particularly acute myelogenous leukemia.This study focused on the effects of AZD1208 on chronic lymphocytic leukemia (CLL) cells. We found that CLL cells exhibited higher levels of PIM2 protein and mRNA compared to normal lymphocytes from healthy donors. When CLL lymphocytes were treated with AZD1208, there was a modest induction of cell death, while healthy lymphocytes showed minimal cytotoxicity. To understand how AZD1208 affects PIM kinase activity, we examined the PIM signaling pathway and its downstream targets. Since CLL cells are generally quiescent in terms of replication, we focused on substrates related to apoptosis, transcription, and translation rather than those involved in the cell cycle.AZD1208 was found to inhibit protein translation by reducing phosphorylation levels of 4E-binding protein 1 (4E-BP1). Additionally, it induced autophagy in these quiescent CLL cells, which aligns with the observed inhibition of protein translation. These findings suggest that AZD1208 may induce cytotoxic effects in CLL cells through mechanisms that inhibit translation and promote AZD1208 autophagy.