Abstract
Multiple myeloma (MM) remains an incurable disease in need of the development of novel therapeutic agents and drug combinations. ABT‐199 is a specific Bcl‐2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co‐expression of Mcl‐1 and Bcl‐xL. These limitations preclude its use in a broader patient population. We have recently found that a sphingosine kinase 2‐specific inhibitor (ABC294640) induces apoptosis in primary human CD138+ cells and MM cell lines. ABC294640 is currently in phase I/II clinical trials for myeloma (clinicaltrials.gov: #NCT01410981). Interestingly, ABC294640 down‐regulates c‐Myc and Mcl‐1, but does not have any effects on Bcl‐2. We first evaluated the combinatorial anti‐myeloma effect of ABC294640 and ABT‐199 in vitro in 7 MM cell lines, all of which harbor no t(11;14) translocation. Combination index calculation demonstrated a synergistic anti‐myeloma effect of the combination of ABC294640 and ABT‐199. This synergistic anti‐myeloma effect was maintained even in the presence of bone marrow (BM) stromal cells. The combination of ABC294640 and ABT‐199 led to enhanced cleavage of PARP and caspase‐3/9 and increased Annexin‐V expression, consistent with the induction of apoptosis by the combination treatment. In addition, the combination of ABC294640 and ABT‐199 resulted in the down‐regulation of the anti‐apoptotic proteins Mcl‐1, Bcl‐2, and Bcl‐xL and the cleavage of Bax and Bid. The combination induced both the mitochondrial mediated‐ and caspase‐mediated apoptosis pathways. Finally, the combination of ABC294640 and ABT‐199 resulted in augmented anti‐myeloma effect in vivo in a mouse xenograft model. These findings demonstrate that the co‐administration of ABC294640 and ABT‐199 exhibits synergistic anti‐myeloma activity in vitro and in vivo, providing justification for a clinical study of this novel combination in patients with relapsed/refractory multiple myeloma.
Highlights
Multiple myeloma (MM) is a malignant plasma cell disorder with no standard curative therapy.[1]
We showed that the SK2 inhibitor (ABC294640) decreased multiple myeloma cell proliferation in vitro and exhibited significant anti-myeloma efficacy in vivo.[4]
Our results demonstrated that the combination of ABC294640 and ABT-1 99 led to dramatic down-regulation of Mcl-1, c-Myc, and Bcl-xL, and activation of both intrinsic and extrinsic apoptosis pathways
Summary
Multiple myeloma (MM) is a malignant plasma cell disorder with no standard curative therapy.[1]. Over the last 2-3 decades, the outcomes and survival of patients with MM have significantly improved largely due to the use of “biologic” agents—immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, and the incorporation of autologous hematopoietic stem-cell transplantation Despite these advances in treatment, MM remains an incurable disease. Overexpression of Mcl-1 has been observed in various cancers including MM and plays a major role in myeloma cell survival and resistance to chemotherapy.[43,44]. Due to these limitations, there has been great interest in combining ABT-199 with other agents to augment ABT-1 99’s activity in patients without a t(11;14) translocation, and to prevent drug resistance to ABT-199. Our findings suggest a role for the combination of ABT-199 and ABC294640 in MM patients
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