Combination of Farnesyl transferase inhibitor (Lonafarnib) and the proteasome inhibitor (Bortezomib) induces synergistic apoptosis in human myeloma

The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple Myeloma (MM) growth is IL-6 dependant, and IK-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/MAPK pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma cell killing. Methods: MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Results: Combination therapy induced synergistic tumor cell death in MM cell lines and primary MM plasma cells. Cell death was rapid, and associated with increased caspase 3, 8, and 9 cleavage and concomitant down regulation of p-AKT. Down regulation of p-AKT was seen only in combination therapy, and not seen with either single agent. Cells transfected with constitutively active p-AKT, wild type AKT or Bcl-2 continued to demonstrate synergistic cell death in response to the combination. The order of addition was critically important supporting bortezomib followed by lonafarnib as the optimal schedule. Conclusion: The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma cell death, and warrants further pre-clinical and clinical studies.