Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma

SIMPLE SUMMARY: The identification of new pharmacological combinations with synergistic effect in multiple myeloma is highly relevant since this is, for the moment, an incurable disease. The high expression of Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases, especially PIM2, in myeloma cells is in agreement with the antiproliferative effect previously shown by the pan-PIM kinase inhibitor PIM447 in these types of cells. Therefore, PIM447 is a good candidate to be studied in new combinations with standard-of-care drugs. In this work, we demonstrate by preclinical studies that PIM447 in combination with the standard treatment pomalidomide + dexamethasone exerts a potent antitumor effect and significantly improves survival with respect to the standard treatment. Our data suggest that these effects are in part mediated by the inhibition of protein translation promoted by this triple combination. These results could be the basis for new clinical trials based on this all-oral combination, which would benefit MM patients. ABSTRACT: Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.