A specific metabolic adaptation has been identified in the cancer cells of some patients with acute myeloid leukaemia (AML), researchers have reported.
The study, published in Nature Communications, defines a new specific metabolic profile related to individuals with the FLT3-ITD+ subtype.
A team jointly supervised by Professor Marta Cascante, from the University of Barcelona in Spain, and Professor Jan Jacob Schuringa, from the University of Groningen in the Netherlands, used metabolomics, proteomics and stable isotope-resolved metabolomics (SIRM) in their research.
They found leukaemic cells in patients with FLT3-ITD+ AML have high levels of the succinate-CoA Ligases enzymes and a high activity of the mitochondrial electron transport chain complex II, which provides energy to the cell metabolism.
Normally, the main raw materials of energy production in mitochondria are pyruvate and other carbohydrates and amino acids that lead to pyruvate, apart from ketone bodies, glutamine, and fatty acids.
However, Prof Cascante said their study also shows for the first time that the cells of this subtype of leukaemia uses the lactate as a substrate for mitochondrial respiration.
“In general, lactate had not been described to date as a subtrate of mitochondrial respiration in tumour cells,” said Prof Cascante. “Therefore, this profile of cancer cells could be sensitive to the simultaneous pharmacological inhibition of complex II of the respiratory chain and lactate transporter,” she added.
The chain of mitochondrial respiration in these leukemic cells could be inhibited pharmacologically with a combination of complex II inhibitors (specifically, TTFA and 3-NPA compounds) and MCT1 lactate transporter inhibitors (CHC and AZD3965).
The researchers say understanding the metabolic profile of a patient’s leukaemia cells could help design new and specific therapies according to the mutations identified at the genetic level.
“Customised medicine, which aims to establish specific therapies for each patient according to the phenotype of their tumour, implies having the best knowledge of each patient’s tumour in order to be able to offer them the best therapeutic option for their specific tumour,” said Prof Cascante.
Erdem A, Marin S, Pereira-Martins DA, Geugien M, Cunningham A, Pruis MG, Weinhäuser I, Gerding A, Bakker BM, Wierenga ATJ, Rego EM, Huls G, Cascante M, Schuringa JJ. (2022) “Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability.” Nature Communications, doi: 10.1038/s41467-022-29639-0
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