Targeting mitochondrial metabolism in acute myeloid leukemia
Madison Rex, Christina Williamson, Kıvanç Birsoy, Martin S. Ta llman, Maximillian Stahl
Abstract
Cancer cells reprogram their metabolism to maintain sustained proliferation, which creates unique metabolic dependencies between malignant and healthy cells that can be exploited for therapy. In acute myeloid leukemia (AML), mitochondrial inhibitors that block tricarboxylic acid cycle enzymes or electron transport chain complexes have recently shown clinical promise. The isocitrate dehydrogenase 1 inhibitor ivosidenib, the isocitrate dehydrogenase 2 inhibitor enasidenib, and the BH3 mimetic venetoclax received FDA approval for treatment of AML in the last few years. Other mitochondrial inhibitors including CPI-613, CB-839, dihydroorotate dehydrogenase inhibitors, IACS-010759, and mubritinib, have shown encouraging preclinical efficacy and are currently being evaluated in clinical trials. In this review, we summarize recent metabolism-based therapies and their ability to target altered cancer metabolism in AML.