TY - JOUR
T1 - Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment
AU - Tabe, Yoko
AU - Konopleva, Marina
N1 - Funding Information:
We thank Amy Ninetto, Scientific Editor, Research Medical Library, MD Anderson Cancer Center, for editing the manuscript.
Publisher Copyright:
© The Author(s) 2023.
PY - 2023
Y1 - 2023
N2 - In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment, acute myeloid leukemia (AML) cells continuously adjust their metabolic state. To meet the biochemical demands of their increased proliferation, AML cells strongly depend on mitochondrial oxidative phosphorylation (OXPHOS). Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation (FAO), which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance. For targeting these metabolic vulnerabilities of AML cells, inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential. Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells, enabling them to acquire resistance against OXPHOS and FAO inhibitors. These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors. Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.
AB - In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment, acute myeloid leukemia (AML) cells continuously adjust their metabolic state. To meet the biochemical demands of their increased proliferation, AML cells strongly depend on mitochondrial oxidative phosphorylation (OXPHOS). Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation (FAO), which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance. For targeting these metabolic vulnerabilities of AML cells, inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential. Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells, enabling them to acquire resistance against OXPHOS and FAO inhibitors. These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors. Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.
KW - acute myeloid leukemia
KW - Bone marrow microenvironment
KW - energy metabolism
KW - fatty acid oxidation
KW - mitochondria
KW - oxidative phosphorylation
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U2 - 10.20517/cdr.2022.133
DO - 10.20517/cdr.2022.133
M3 - Review article
C2 - 37065866
AN - SCOPUS:85158107182
SN - 2578-532X
VL - 6
SP - 138
EP - 150
JO - Cancer Drug Resistance
JF - Cancer Drug Resistance
IS - 1
ER -