Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment

Yoko Tabe; Marina Konopleva

doi:10.20517/cdr.2022.133

Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment

Cancer Drug Resist. 2023 Mar 14;6(1):138-150. doi: 10.20517/cdr.2022.133. eCollection 2023.

Authors

Yoko Tabe^{1

2}, Marina Konopleva^{2

3}

Affiliations

¹ Department of Laboratory Medicine, Juntendo University, Tokyo 112-8421, Japan.
² Department of Medicine (Oncology) and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
³ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Abstract

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.

Keywords: Bone marrow microenvironment; acute myeloid leukemia; energy metabolism; fatty acid oxidation; mitochondria; oxidative phosphorylation.

Publication types

Review