Metabolic reprogramming represents a targetable mechanism to overcome acquired resistance to venetoclax in acute myeloid leukemia

  • Biochim Biophys Acta Mol Basis Dis. 2026 Jan;1872(1):168065. doi: 10.1016/j.bbadis.2025.168065.
Gustavo Nery de Queiroz  1 ,  Keli Lima  2 ,  Marcella Cipelli  3 ,  Victoria Tomaz  4 ,  Luiz Gustavo Ferreira Cortez  4 ,  Marina de Franca Basto Silva  4 ,  Rafael Lucas Muniz Guedes  4 ,  Paulo Vidal Campregher  4 ,  Eduardo Magalhães Rego  5 ,  Niels Olsen Saraiva Câmara  3 ,  Leticia Veras Costa-Lotufo  1 ,  João Agostinho Machado-Neto  6
Affiliations
  • 1. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
  • 2. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Laboratory of Medical Research in Pathogenesis and Target Therapy in Onco-Immuno-Hematology, Department of Internal Medicine, Division of Hematology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
  • 3. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
  • 4. Hospital Israelita Albert Einstein, São Paulo, Brazil.
  • 5. Laboratory of Medical Research in Pathogenesis and Target Therapy in Onco-Immuno-Hematology, Department of Internal Medicine, Division of Hematology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil; Center for Cell Therapy, Foundation for Research Support of the State of São Paulo, Ribeirão Preto, SP, Brazil.
  • 6. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: [email protected].
PMID: 41043531 DOI: 10.1016/j.bbadis.2025.168065
Abstract

Acute myeloid leukemia (AML) often develops resistance to the BCL2 inhibitor venetoclax through metabolic reprogramming. This study established acquired venetoclax-resistant AML models (MV4-11VR and MOLM-13VR) to explore resistance mechanisms and therapeutic strategies. Cell viability and Apoptosis assays revealed robust acquired resistance to venetoclax upon intermittent drug exposure. Metabolic profiling revealed distinct adaptations: MV4-11VR cells favored glycolysis, while MOLM-13VR cells increased Oxidative Phosphorylation. Proteomic analysis supported these findings, showing pathway enrichment for carbohydrate metabolism in MV4-11VR and aerobic energy production in MOLM-13VR. Despite these differences, both models shared hyperactivation of the PI3K/Akt/mTOR pathway, as shown by RPS6 hyperphosphorylation. Apoptotic regulation also diverged between the cellular models in relation to modulated BCL2-related genes and activation of the MAPK signaling pathway. Targeting these metabolic changes with metformin (a mitochondrial complex I inhibitor) or KPT-9274 (a NAMPT Inhibitor) re-sensitized resistant cells to venetoclax. Combination treatments showed strong synergy and near-complete cell elimination. These results highlight metabolic reprogramming as a heterogeneous but targetable resistance mechanism and support combining metabolic inhibitors with BCL2 blockade to treat refractory AML.

Keywords
Acute myeloid leukemia; Glycolysis; Metabolic reprogramming; OXPHOS; Targeted therapy; Venetoclax resistance.
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