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

2020; Nature Portfolio; Volume: 1; Issue: 12 Linguagem: Inglês

10.1038/s43018-020-00126-z

2662-1347

Brett M. Stevens, Courtney L. Jones, Daniel A. Pollyea, Rachel Culp‐Hill, Angelo D’Alessandro, Amanda Winters, Anna Krug, Diana Abbott, Madeline Goosman, Shanshan Pei, Haobin Ye, Austin E. Gillen, Michael W. Becker, Michael R. Savona, Clayton A. Smith, Craig T. Jordan,

Histone Deacetylase Inhibitors Research

Venetoclax with azacitidine (ven/aza) has emerged as a promising regimen for acute myeloid leukemia (AML), with a high percentage of clinical remissions in newly diagnosed patients. However, approximately 30% of newly diagnosed and the majority of relapsed patients 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 which is required in primitive AML cells to drive oxidative phosphorylation. Herein we demonstrate that resistance to ven/aza occurs via up-regulation of fatty acid oxidation (FAO), which occurs 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.