Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia

by Selleckchem | Apr 05 2023

Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and therapy resistance. Devimistat is a novel agent that inhibits pyruvate dehydrogenase complex (PDH). A phase III clinical trial in AML patients combining devimistat and chemotherapy was terminated for futility, suggesting AML cells were able to circumvent the metabolic inhibition of devimistat. The means by which AML cells resist PDH inhibition is unknown. AML cell lines treated with devimistat or deleted for the essential PDH subunit, PDHA, showed a decrease in glycolysis and decreased glucose uptake due to a reduction of the glucose transporter GLUT1 and hexokinase II. Both devimistat-treated and PDHA knockout cells displayed increased sensitivity to 2-deoxyglucose, demonstrating reliance on residual glycolysis. The rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly upregulated in devimistat-treated cells, and its inhibition increased sensitivity to devimistat. The gluconeogenic amino acids glutamine and asparagine protected AML cells from devimistat. Non-glycolytic sources of acetyl-CoA were also important with fatty acid oxidation, ATP citrate lyase (ACLY) and acyl-CoA synthetase short chain family member 2 (ACSS2) contributing to resistance. Finally, devimistat reduced fatty acid synthase (FASN) activity. Taken together, this suggests that AML cells compensate for PDH and glycolysis inhibition by gluconeogenesis for maintenance of essential glycolytic intermediates and fatty acid oxidation, ACLY and ACSS2 for non-glycolytic production of acetyl-CoA. Strategies to target these escape pathways should be explored in AML.

Comments：

Acute myeloid leukemia (AML) is a challenging disease to treat, as it is aggressive and often resistant to chemotherapy. Devimistat, a novel agent that inhibits pyruvate dehydrogenase complex (PDH), was tested in a phase III clinical trial in combination with chemotherapy in AML patients. However, the trial was terminated due to futility, suggesting that AML cells were able to circumvent the metabolic inhibition of devimistat.

Further investigation revealed that AML cells compensate for the inhibition of PDH and glycolysis by activating alternative metabolic pathways, such as gluconeogenesis, fatty acid oxidation, and non-glycolytic sources of acetyl-CoA. AML cells treated with devimistat or deleted for the essential PDH subunit, PDHA, showed a decrease in glycolysis and glucose uptake due to a reduction of the glucose transporter GLUT1 and hexokinase II. However, both devimistat-treated and PDHA knockout cells displayed increased sensitivity to 2-deoxyglucose, indicating their reliance on residual glycolysis.

Interestingly, the rate-limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly upregulated in devimistat-treated cells, and its inhibition increased sensitivity to devimistat. Additionally, the gluconeogenic amino acids glutamine and asparagine protected AML cells from devimistat. Non-glycolytic sources of acetyl-CoA were also important, with fatty acid oxidation, ATP citrate lyase (ACLY), and acyl-CoA synthetase short chain family member 2 (ACSS2) contributing to resistance. Finally, devimistat reduced fatty acid synthase (FASN) activity.

Taken together, these findings suggest that AML cells can escape the metabolic inhibition of devimistat by activating alternative metabolic pathways. Therefore, targeting these escape pathways may be a potential strategy to improve the effectiveness of devimistat in AML treatment.