Dual sphingosine kinase and Bcl-2 inhibition exhibits synergistic cell death in acute myeloid leukemia
- Centre for Cancer Biology, University of South Australia, CRI Building, North Terrance, Adelaide, SA 5001, Australia.
- Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Pro-survival Bcl-2 family proteins such as Mcl-1 and Bcl-2 have garnered significant interest as therapeutic targets due to their up-regulation in many cancers, including acute myeloid leukaemia (AML), leading to enhanced cancer cell survival. Small molecule inhibitors such as the selective Bcl-2 inhibitor, Venetoclax, are very effective in some cancers that are highly on Bcl-2, but have demonstrated poor single agent efficacy in AML due to these cells being highly dependent on Mcl-1, which is not targeted by this agent. Sphingosine kinase 1 (SK1) is a signalling enzyme with established roles in oncogenesis and has recently emerged as a potential therapeutic target in leukaemia. We recently demonstrated that the selective SK1 inhibitor, MP-A08 exhibits anti-leukemic activity in vitro and in vivo using patient-derived AML xenograft models. MP-A08-mediated cytotoxicity in AML cells correlated with a reduction in Mcl-1 levels, as well as upregulation of BH3 only proteins. Here, we found that combinational therapies with MP-A08 and Venetoclax induced synergistic cell death in AML cell lines and patient samples. Mechanistically, MP-A08 induces transcriptional upregulation of BH3-only protein, Noxa and formation of Noxa/Mcl-1 complexes. MP-A08 appears to exert its cytotoxicity in AML cells through loss of Mcl-1 as a consequence of Noxa binding. Using patient-derived xenografts, we demonstrate that MP-A08 and Venetoclax treatment exhibits anti-leukemic activity in vivo providing pre-clinical evidence to target SK1 and Bcl-2 in AML.