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

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

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: jamachadoneto@usp.br.
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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