Abstract
Abstract 2909
Multiple myeloma (MM) is a plasma cell malignancy and is the second most common hematological neoplasm in the Western World. Despite the discovery of several highly effective chemotherapy agents, MM remains an incurable disease, suggesting the urgent need for better understanding the disease's pathogenesis and for developing therapeutic agents that target novel molecular pathways. Pim (proviral insertion in murine lymphoma) kinases (Pim-1, -2 and -3) are constitutively active, oncogenic serine/threonine protein kinases that promote early transformation and tumor progression in hematological malignancies and in solid tumors including prostate cancer and colon cancer. In the current study, we characterized Pim expression and investigated the therapeutic potential of small molecule Pim kinase inhibitors in the treatment of MM. We found that Pim kinases are highly expressed in several MM cell lines (NCIH929, OPM-1, RPMI8226, U266 and MM1.R). Furthermore, Pim kinases were up-regulated in freshly isolated primary CD138+ myeloma cells (n = 4) when compared to CD138− cells (panel A). The predominant Pim kinase isoform (Pim-1, -2 or -3) varies among MM cell lines and among different patients. Two Pim kinase inhibitors, SMI-4a (selective small molecule Pim-1 and Pim-3 inhibitor) and 10058-F4 (Pim-3 and Pim-1 inhibitor) effectively inhibited myeloma cell growth, including steroid resistant MM1.R myeloma cells, with IC50s in the ∼10 mM range. Both SMI-4a and 10058-F4 induced apoptotic cell death in myeloma cells as measured by Annexin-V staining, caspase-9 activation and PARP cleavage in a dose dependent manner. To further dissect their mechanisms of action, we investigated the effects of SMI-4a and 10058-F4 on several cellular signaling pathways that are critical to the survival, cell cycle progression and proliferation of MM cells. Our data indicated that both SMI-4a and 10058-F4 reduce c-Myc protein expression levels and down-regulate the antiapoptotic Mcl-1 protein in MM cells (panel B). Our data also showed that MM cells treated with SMI-4a or 10058-F4 significantly reduced mTOR signaling as indicatd by decreased phosphorylation of 4E-BP1 and Cp70 S6 kinase α, the two common mTOR substrates. However, SMI-4a and 10058-F4 had no effect on the cell cycle regulation protein (p27Kip1) or heat shock protein 90. In summary, our data demonstrate that Pim inhibitors affect the survival and proliferation of myeloma cells and represent a potentially effective, novel strategy for the treatment of MM. We are currently performing in vivo studies to evaluate the therapeutic effects of Pim inhibitor in MM animal models (i.e, XPB-1s transgenic mouse model and NOD/SCID xenograft mouse model).
No relevant conflicts of interest to declare.
