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.

Venetoclax 与阿扎胞苷 (ven/aza) 已成为治疗急性髓性白血病 (AML) 的一种有前途的治疗方案，在新诊断的患者中临床缓解率很高。然而，大约 30% 的新诊断患者和大多数复发患者在使用 ven/aza 后未达到缓解。我们之前报道过 ven/aza 的功效是基于通过抑制氨基酸代谢的机制根除 AML 干细胞，这是原始 AML 细胞驱动氧化磷酸化所需的过程。在这里，我们证明了对 ven/aza 的抗性通过脂肪酸氧化 (FAO) 的上调发生，这可能是由于 RAS 通路突变或作为复发性疾病的补偿性适应而发生的。粮农组织的利用消除了对氨基酸代谢的需要，从而使 ven/aza 无效。对FAO的药理抑制可恢复耐药AML细胞对ven/aza的敏感性。我们建议将抑制粮农组织作为解决 ven/aza 抗性的治疗策略。