文章目录

脂肪酸代谢是急性髓系白血病干细胞venetoclax耐药的基础

原文发布日期：2020-10-26

英文摘要：

摘要翻译：

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文章：

脂肪酸代谢是急性髓系白血病干细胞venetoclax耐药的基础

Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells

原文发布日期：2020-10-26

英文摘要：

Venetoclax with azacitidine (ven/aza) has emerged as a promising treatment regimen for acute myeloid leukemia (AML), with a high percentage of clinical remissions in newly diagnosed patients. However, approximately 30% of newly diagnosed patients and the majority of patients who have relapsed do not achieve remission with ven/aza. We previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process required in primitive AML cells to drive oxidative phosphorylation. Herein we demonstrate that resistance to ven/aza occurs via upregulation of fatty acid oxidation (FAO), which occurs either due to RAS pathway mutations or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism, thereby rendering ven/aza ineffective. Pharmacological inhibition of FAO restores sensitivity to ven/aza in drug-resistant AML cells. We propose inhibition of FAO as a therapeutic strategy to address ven/aza resistance.

摘要翻译：

维拉帕尼联合替美特瑞（ven/aza）作为一种有前途的治疗方案，在新诊断急性髓系白血病（AML）患者中表现出显著缓解率。然而，约30%的新诊断患者和大部分复发患者未能通过维/替获得缓解。我们之前研究表明，维/替疗效依赖于 primitive AML细胞驱动氧化磷酸化所需的AML干细胞被消除。在此研究中，我们表明耐药性发生于脂肪酸氧化作用上调表达的情况下，这可能源于RAS通路突变或复发性疾病中的适应性调整。使用脂肪酸氧化作用避免了对氨基酸代谢的需求，因而使维/替无效。药物抑制脂肪酸氧化作用可使耐药性髓系白血病细胞恢复对维拉帕尼联合替美特瑞的敏感性。我们提出抑制脂肪酸氧化作为治疗耐药性的策略。