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

IF 4.6 Q1 ONCOLOGY 癌症耐药(英文) Pub Date : 2023-01-01 DOI:10.20517/cdr.2022.133
Yoko Tabe, Marina Konopleva
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引用次数: 1

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.

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骨髓微环境中残留的AML细胞对能量代谢靶向治疗的抵抗。
急性髓性白血病(AML)细胞根据骨髓微环境中营养物质和氧的可用性的变化,不断调整其代谢状态。为了满足其增殖增加的生化需求,AML细胞强烈依赖线粒体氧化磷酸化(OXPHOS)。最近的数据表明,AML细胞的一个子集保持静止,并通过脂肪酸氧化(FAO)的代谢激活存活,这导致线粒体OXPHOS解偶联并促进化学耐药。针对AML细胞的这些代谢脆弱性,OXPHOS和FAO的抑制剂已被开发并研究其治疗潜力。最近的实验和临床证据表明,耐药AML细胞和白血病干细胞通过与骨髓基质细胞的相互作用重新连接代谢途径,使它们能够获得对OXPHOS和FAO抑制剂的耐药性。这些获得性耐药机制补偿了抑制剂的代谢靶向作用。目前正在开发几种与OXPHOS和FAO抑制剂联合使用的化疗/靶向治疗方案,以针对这些代偿途径。
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