State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
College of Pharmacy, Fudan University, Shanghai, 210023, China.
Nat Commun. 2023 Apr 5;14(1):1882. doi: 10.1038/s41467-023-37381-4.
The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBPα activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBPα activation limit FLT3i efficacy, while its inactivation synergistically enhances FLT3i action in cellular and female animal models. We then perform an in silico screen and identify that guanfacine, an antihypertensive medication, mimics C/EBPα inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBPα activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBPα activation as a targetable PR mechanism and support clinical studies aimed at testing the combination of guanfacine with FLT3i in overcoming PR and enhancing the efficacy of FLT3i therapy.
FLT3 内部串联重复（FLT3-ITD）急性髓系白血病（AML）的治疗结果自 FLT3 抑制剂（FLT3i）获批以来已有改善。然而，约 30-50%的患者对 FLT3i 表现出原发性耐药（PR），其机制尚不清楚，这是一个迫切的临床未满足的需求。在这里，我们通过分析 Vizome 中原发性 AML 患者样本的数据，确定 C/EBPα 激活是 PR 的首要特征。C/EBPα 激活限制了 FLT3i 的疗效，而其失活则协同增强了 FLT3i 在细胞和雌性动物模型中的作用。我们随后进行了一项计算机筛选，并鉴定出胍法辛，一种降压药物，可模拟 C/EBPα 失活。此外，胍法辛在体外和体内与 FLT3i 具有协同作用。最后，我们在另一组 FLT3-ITD 患者中确定了 C/EBPα 激活在 PR 中的作用。这些发现强调了 C/EBPα 激活作为一种可靶向的 PR 机制，并支持旨在测试胍法辛与 FLT3i 联合应用以克服 PR 并增强 FLT3i 治疗效果的临床研究。
