Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia

Abstract

Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy; we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.

Keywords: DHODH; IDH; OXPHOS; leukemia stem cells; mesenchymal stromal cells.

Figure 1

List of clinical trials for metabolic inhibitors in AML. AML: Acute myeloid leukemia; ClpP: caseinolytic protease proteolytic subunit; CMML: chronic myelomonocytic leukemia; DHODH: dihydroorotate dehydrogenase; ETC: electron transport chain; IDH: isocitrate dehydrogenase enzyme; MDS: myelodysplastic syndromes; OXPHOS: oxidative phosphorylation; TCA: tricarboxylic acid cycle.

Figure 2

Overview of cellular metabolic pathways and their crosstalk -including: (1) glycolysis; (2) TCA cycle; (3) OXPHOS; (4) glutaminolysis; (5) nucleic acid biosynthesis; (6) lipid synthesis; (7) fatty acid import and oxidation; (8) ROS mitigation by GSH; (9) ferroptosis. ACC: Ac-CoA carboxylase; ACLY: ATP citrate lyase; ADP: adenosine diphosphate; ATP: denosine triphosphate; α-KG: α-ketoglutarate; CAT: carnitine acetyltransferase; CPT1: carnitine palmitoyltransferase 1; CPT2: carnitine palmitoyltransferase 2; DHO: dihydroorotate; DHODH: dihydroorotate dehydrogenase; FAD: flavin adenine dinucleotide; FASN: FA synthase; GSH: glutathione; IDH: isocitrate dehydrogenase enzyme; GCL: glutamate-cysteine ligase; GSS: glutathione synthetase; GLS1: glutaminase 1; NAD: nicotinamide adenine dinucleotide; NADH: nicotinamide adenine dinucleotide (NAD) + hydrogen (H); MUFA: monounsaturated fatty acid; OXPHOS: oxidative phosphorylation; PUFA: polyunsaturated fatty acid; ROS: reactive oxygen species; TCA: tricarboxylic acid cycle; UMP: uridine monophosphate.