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

Autor: Stevens BM; Division of Hematology, University of Colorado Denver, Aurora, CO, USA., Jones CL; Division of Hematology, University of Colorado Denver, Aurora, CO, USA., Pollyea DA; Division of Hematology, University of Colorado Denver, Aurora, CO, USA., Culp-Hill R; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO, USA., D'Alessandro A; Division of Hematology, University of Colorado Denver, Aurora, CO, USA.; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO, USA., Winters A; Division of Pediatric Hematology and Oncology, University of Colorado Denver, Aurora, CO, USA., Krug A; Division of Hematology, University of Colorado Denver, Aurora, CO, USA., Abbott D; Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA., Goosman M; Division of Hematology, University of Colorado Denver, Aurora, CO, USA., Pei S; Division of Hematology, University of Colorado Denver, Aurora, CO, USA., Ye H; Division of Hematology, University of Colorado Denver, Aurora, CO, USA., Gillen AE; RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA., Becker MW; Department of Medicine, James P. Wilmot Cancer Center, Rochester, NY, USA., Savona MR; Department of Internal Medicine, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA., Smith C; Division of Hematology, University of Colorado Denver, Aurora, CO, USA., Jordan CT; Division of Hematology, University of Colorado Denver, Aurora, CO, USA. craig.jordan@cuanschutz.edu.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2020 Dec; Vol. 1 (12), pp. 1176-1187. Date of Electronic Publication: 2020 Oct 26.
DOI: 10.1038/s43018-020-00126-z
Abstrakt: 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.
Competing Interests: Declaration of Interests: The authors declare the following competing interests:
Databáze: MEDLINE
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