Division of Hematology, University of Colorado Denver, Aurora, CO, USA.
Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO, USA.
Nat Cancer. 2020 Dec;1(12):1176-1187. doi: 10.1038/s43018-020-00126-z. Epub 2020 Oct 26.
Venetoclax with azacitidine (ven/aza) has emerged as a promising regimen for acute myeloid leukemia (AML), with a high percentage of clinical remissions in newly diagnosed patients. However, approximately 30% of newly diagnosed and the majority of relapsed patients 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 which is required in primitive AML cells to drive oxidative phosphorylation. Herein we demonstrate that resistance to ven/aza occurs via up-regulation of fatty acid oxidation (FAO), which occurs 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.
维奈托克联合阿扎胞苷（ven/aza）已成为急性髓系白血病（AML）有前途的治疗方案，在新诊断的患者中有很高的临床缓解率。然而，大约 30%的新诊断和大多数复发的患者不能通过 ven/aza 达到缓解。我们之前报道过，ven/aza 的疗效是基于通过抑制氨基酸代谢来消除 AML 干细胞，这个过程在原始 AML 细胞中是必需的，以驱动氧化磷酸化。在此，我们证明对 ven/aza 的耐药性是通过脂肪酸氧化（FAO）的上调而产生的，这种上调是由于 RAS 途径突变或在复发疾病中作为一种代偿性适应而发生的。FAO 的利用消除了对氨基酸代谢的需求，从而使 ven/aza 失去作用。抑制 FAO 的药理学抑制作用恢复了耐药 AML 细胞对 ven/aza 的敏感性。我们提出抑制 FAO 作为一种治疗策略来解决 ven/aza 耐药性。
