Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

Purpose: To show that 8-Cl-Ado can target FAO and synergizes with VEN to significantly decrease the oxygen consumption rate (OCR) and in turn OXPHOS in CD34-enriched AML cells. Methods: Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Results: We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p=0.006). Conclusion: Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML. Overall design: We treated MV4-11 AML cells with 250 nM 8-chloro-adenosine, 10 nM venetoclax, combination of both or control, for 4h, 12 h and 24h, all in duplicates. combination of both or control, for 12 h and 24h, all in duplicates. We also treated KG-1a AML cells with 500 nM 8-chloro-adenosine, 10 nM venetoclax, combination of both or control, for 12 h and 24h, all in duplicates. Finally, we treated primary AML blasts from 2 different patients (14269-HTB19-005, and 14269-HTB20-006) with 500 nM 8-chloro-adenosine, 10 nM venetoclax, combination of both or control, for 24h