3004 – ACUTE MYELOID LEUKEMIA CELLS REQUIRE 18-CARBON LONG FATTY ACIDS FOR PROTEIN S-ACYLATION TO MAINTAIN MITOCHONDRIAL ACTIVITY AND METABOLIC PLASTICITY

Abstract

While cancer cells have been identified to have a metabolism distinct from normal cells for almost a century, the clinical success of targeting metabolic enzymes for cancer therapy remains limited. A key reason for this is the ability of cells to rewire their metabolism and adapt to the blockage of a single pathway. Here, we use acute myeloid leukemia (AML), a highly lethal blood cancer, as a model to investigate and target metabolic plasticity. We treated human AML cell lines with combinations of pharmacological compounds targeting metabolic enzymes across central carbon metabolism. An unexpected synthetic lethality was observed when AML cells were simultaneously treated with BPTES, an inhibitor of glutaminase, the rate-limiting enzyme in glutamine catabolism, and TOFA, an inhibitor of acetyl-CoA carboxylase 1, a key enzyme in de novo lipogenesis. Sensitivity to this metabolic inhibitor combination was equally seen in primary AML patient samples, but healthy hematopoietic stem and progenitor cells were not affected. Stable isotope tracing and lipidomics experiments revealed that AML cells are highly lipogenic and have a distinct lipid profile characterized by a high degree of fatty acid saturation. However, we unexpectedly found that the cytotoxic effects of TOFA are not due to its inhibition of lipogenesis, but because this compound also inhibits protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 18-carbon long fatty acids and is essential to maintain correct mitochondrial function and allow metabolic adaptation to inhibition of glutaminolysis. Extended screening further showed that not only AML, but many different cancer types are sensitive to combined inhibition of protein S-acylation and glutaminolysis, highlighting this as a promising strategy to overcome metabolic plasticity and selectively eliminate cancer cells.