硬脂酰辅酶A去饱和酶抑制对显示高水平从头脂肪酸生物合成和去饱和的急性髓系白血病具有毒性。
Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation.
发表日期：2024 Aug 26
作者：
Vilma Dembitz, Hannah Lawson, Richard Burt, Sirisha Natani, Céline Philippe, Sophie C James, Samantha Atkinson, Jozef Durko, Lydia M Wang, Joana Campos, Aoife M S Magee, Keith Woodley, Michael J Austin, Ana Rio-Machin, Pedro Casado, Findlay Bewicke-Copley, Giovanny Rodriguez Blanco, Diego Pereira-Martins, Lieve Oudejans, Emeline Boet, Alex von Kriegsheim, Juerg Schwaller, Andrew J Finch, Bela Patel, Jean-Emmanuel Sarry, Jerome Tamburini, Jan Jacob Schuringa, Lori Hazlehurst, John A Copland Iii, Mariia Yuneva, Barrie Peck, Pedro Cutillas, Jude Fitzgibbon, Kevin Rouault-Pierre, Kamil Kranc, Paolo Gallipoli
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
为了改善急性髓系白血病 (AML) 患者的预后，需要识别特定的、治疗上可行的脆弱性（理想情况下存在于多种突变背景中）。我们将脂肪酸 (FA) 去饱和的关键酶硬脂酰辅酶 A 去饱和酶 (SCD) 确定为患者预后的预测指标，并使用临床级抑制剂 SSI-4 表明 SCD 抑制 (SCDi) 是一种治疗脆弱性跨体外和体内多种 AML 模型。多组学分析表明 SCDi 会引起脂毒性，从而通过多效性效应诱导 AML 细胞死亡。对 SCDi 的敏感性与 AML 对 FA 去饱和的依赖性相关，无论突变情况如何，并且受 FA 生物合成活性的调节。最后，我们发现脂毒性会增加化疗引起的 DNA 损伤，并且标准化疗进一步使 AML 细胞对 SCDi 敏感。我们的工作支持开发 AML 中的 FA 去饱和酶抑制剂，同时强调识别反应的预测生物标志物和经过生物学验证的联合疗法的重要性，以实现其全部治疗潜力。© 2024。作者。
Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.© 2024. The Author(s).