Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity

SIMPLE SUMMARY: Multiple myeloma is a bone marrow cancer that represents a severe health threat. The drugs used nowadays in chemotherapy often encounter resistance leading to a dramatic loss of their efficacy, which consequently affects patients’ survival. Previous studies have shown that the protein kinase R (PKR)-like ER kinase (PERK) pathway, which is one of the three branches of the unfolded protein response, is highly activated in multiple myeloma, possibly contributing to the chemotherapy resistance that these patients develop. In this study, we have used the compound GSK2606414, which is a PERK inhibitor, and found that myeloma cells are highly sensitive to this molecule. These effects were more pronounced when the inhibitor was used in combination with an anti-myeloma drug such as the proteasome inhibitor bortezomib, suggesting that the PERK pathway could be a potential therapeutic target for the treatment of multiple myeloma patients. ABSTRACT: Due to increased immunoglobulin production and uncontrolled proliferation, multiple myeloma (MM) plasma cells develop a phenotype of deregulated unfolded protein response (UPR). The eIF2-alpha kinase 3 [EIF2αK3, protein kinase R (PKR)-like ER kinase (PERK)], the third known sensor of endoplasmic reticulum (ER) stress, is a serine-threonine kinase and, like the other two UPR-related proteins, i.e., IRE1 and ATF6, it is bound to the ER membrane. MM, like other tumors showing uncontrolled protein secretion, is highly dependent to UPR for survival; thus, inhibition of PERK can be an effective strategy to suppress growth of malignant plasma cells. Here, we have used GSK2606414, an ATP-competitive potent PERK inhibitor, and found significant anti-proliferative and apoptotic effects in a panel of MM cell lines. These effects were accompanied by the downregulation of key components of the PERK pathway as well as of other UPR elements. Consistently, PERK gene expression silencing significantly increased cell death in MM cells, highlighting the importance of PERK signaling in MM biology. Moreover, GSK2606414, in combination with the proteasome inhibitor bortezomib, exerted an additive toxic effect in MM cells. Overall, our data suggest that PERK inhibition could represent a novel combinatorial therapeutic approach in MM.