Dual sphingosine kinase and Bcl-2 inhibition exhibits synergistic cell death in acute myeloid leukemia

Lewis AC1, Tea M1, Wallington-Beddoe CT1, Anderson D2, Creek D2, Powell JA1 and Pitson SM1

  1. Centre for Cancer Biology, University of South Australia, CRI Building, North Terrance, Adelaide, SA 5001, Australia.
  2. 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.