Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells

Venetoclax with azacitidine (ven/aza) has emerged as a promising treatment regimen for acute myeloid leukemia (AML), with a high percentage of clinical remissions in newly diagnosed patients. However, approximately 30% of newly diagnosed patients and the majority of patients who have relapsed do not achieve remission with ven/aza. We previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process required in primitive AML cells to drive oxidative phosphorylation. Herein we demonstrate that resistance to ven/aza occurs via upregulation of fatty acid oxidation (FAO), which occurs either due to RAS pathway mutations or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism, thereby rendering ven/aza ineffective. Pharmacological inhibition of FAO restores sensitivity to ven/aza in drug-resistant AML cells. We propose inhibition of FAO as a therapeutic strategy to address ven/aza resistance. Jordan and colleagues show the role of increased fatty acid metabolism in AML stem cells, in both intrinsic and acquired resistance to combination venetoclax and azacitidine, and find that cells can be re-sensitized by inhibiting fatty acid oxidation.