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Updated: Mar 17, 2026
Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
Published on: June 6, 2025
Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells
Nithya Balasundaram1,2, Ayşegül Erdem1,2, Azeem Sharda3,4,5
1Cellular Metabolism and Microenvironment Laboratory, de Duve Institute, UCLouvain, Brussels, Belgium.
Abstract:
Though cancer cells' altered metabolism has been recognized for a century, the clinical success of metabolic targeting remains limited due to metabolic plasticity. Here, we use acute myeloid leukemia (AML) as a model to investigate this adaptability through combinatorial metabolic compound screening. Synthetic lethality emerged when AML cells were simultaneously treated with a glutaminase inhibitor and TOFA, a hypolipidemic agent. Sensitivity to this combination was also seen in primary patient samples and in other cancer types, while healthy hematopoietic progenitors were not affected. Unexpectedly, we discovered that TOFA acts through a non-canonical inhibition of protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 16-to-18 carbon long fatty acids and is essential to maintain mitochondrial respiration upon glutaminolysis inhibition. Healthy cells in contrast have high intrinsic metabolic flexibility independent of S-acylation. Our results expose a unique mechanism of metabolic plasticity in cancer that could be targeted to enhance metabolic anti-cancer therapies.
Insights
Targeting cancer cell metabolism, specifically acute myeloid leukemia (AML), using a glutaminase inhibitor and TOFA revealed synthetic lethality. This combination exploits cancer
Area of Science:
- Cancer Biology
- Metabolic Pathways
- Drug Discovery
Background:
- Altered cancer cell metabolism is a hallmark of cancer, known for a century.
- Metabolic plasticity limits the clinical success of targeted anti-cancer therapies.
- Acute myeloid leukemia (AML) serves as a model to study metabolic adaptability.
Purpose of the Study:
- To investigate metabolic adaptability in cancer using combinatorial metabolic compound screening.
- To identify novel therapeutic strategies targeting cancer-specific metabolic vulnerabilities.
- To explore the mechanism behind metabolic plasticity in AML.
Main Methods:
- Combinatorial screening of metabolic compounds in AML cells.
- Treatment with a glutaminase inhibitor and TOFA (a hypolipidemic agent).
- Assessment of sensitivity in primary patient samples and other cancer types.
- Investigation of TOFA's non-canonical mechanism of action.
Main Results:
- Synthetic lethality was observed in AML cells treated with a glutaminase inhibitor and TOFA.
- This drug combination showed sensitivity in primary AML patient samples and other cancer types, sparing healthy cells.
- TOFA was found to non-canonically inhibit protein S-acyltransferases, crucial for mitochondrial respiration in AML cells upon glutaminolysis inhibition.
Conclusions:
- A novel therapeutic strategy targeting metabolic plasticity in cancer, specifically AML, has been identified.
- The combination of a glutaminase inhibitor and TOFA exploits cancer-specific metabolic vulnerabilities.
- Understanding the role of protein S-acylation in cancer metabolism opens new avenues for anti-cancer drug development.
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