Abstract 4800: Pyruvate dehydrogenase inhibition leads to decreased glycolysis and increased reliance on asparagine in acute myeloid leukemia

Abstract

Abstract Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and chemotherapy resistance. Devimistat (CPI-613 ®) is a novel agent that inhibits two key tricarboxylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). Our lab has shown that genetic and pharmacologic inhibition of PDH sensitizes cells to chemotherapy and recent clinical trials of chemotherapy plus devimistat have been promising. However, the means by which AML cells adapt to PDH loss during devimistat treatment is unknown. AML cells with PDH deleted by CRISPR-Cas9 (PDH KO) show decreased mitochondrial oxygen consumption, membrane potential and altered mitochondrial morphology. Surprisingly, PDH KO cells also showed decreased glycolytic rates. In order to explore this mechanism we assessed glucose uptake and found PDH KO cells had significantly less glucose uptake. We next assessed expression of hexokinase II, a key enzyme that commits glucose retention in the cell, in PDH KO and devimistat treated cells. Strikingly, we found that hexokinase II expression was decreased in PDH KO cells, which was rescued with proteasomal inhibition. Consistent with disruption of the protective interaction between mitochondrial membrane channel VDAC1 and HKII. However, PDH KO and devimistat treated cells are more sensitive to the glycolytic inhibitor 2-deoxy-D-glucose. This indicates that even though TCA cycle inhibition decreases glycolysis through loss of HKII, the cells are still reliant on the activity that remains. Cells can supplement TCA cycle intermediates through amino acid metabolism. Two key amino acids, asparagine and glutamate, were reintroduced to devimistat treated, amino acid starved, AML cells and asparagine significantly rescued the cells. Asparaginase, which converts asparagine into aspartic acid and ammonia, significantly increased sensitivity to genetic and pharmacological inhibition of PDH in AML cells. This indicates that glycolysis inhibition and amino acid deprivation in combination with devimistat-mediated PDH inhibition should be further explored in clinical trials. Citation Format: Rebecca Anderson, Kristin M. Pladna, Timothy S. Pardee. Pyruvate dehydrogenase inhibition leads to decreased glycolysis and increased reliance on asparagine in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4800.