Department of Hematology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.
Department of Hematology, Guangzhou First People's Hospital, Guangzhou, 510180, Guangdong, China.
Cell Commun Signal. 2024 Jul 8;22(1):355. doi: 10.1186/s12964-024-01729-0.
BACKGROUND: FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a common mutation type in acute myeloid leukemia (AML) and is usually associated with poor patient prognosis. With advancements in molecular diagnostics and the development of tyrosine kinase inhibitors (TKI), the overall survival (OS) of AML patients with FLT3-ITD mutations has been prolonged to some extent, but relapse and drug resistance are still substantial challenges. Ningetinib is a novel TKI against various kinases in relation to tumour pathogenesis and is undergoing clinical trials of lung cancer. In this study, we explored the antitumor activity of ningetinib against AML with FLT3 mutations both in vivo and in vitro. METHODS: Cell proliferation assays were performed in AML cell lines and Ba/F3 cells expressing various FLT3 mutations to validate the antileukemic activity of ningetinib in vitro. Immunoblot assays were used to verify the effect of ningetinib on the FLT3 protein and downstream pathways. Molecular docking and CETSA were used to validate the interaction of ningetinib with target proteins. The survival benefit of ningetinib in vivo was assessed in Ba/F3-FLT3-ITD-, MOLM13, Ba/F3-FLT3-ITD-F691L-, MOLM13-FLT3-ITD-F691L-induced leukemia mouse models. We also used patient-derived primary cells to determine the efficacy of ningetinib. RESULTS: Ningetinib inhibited cell proliferation, blocked the cell cycle, induced apoptosis and bound FLT3 to inhibit its downstream signaling pathways, including the STAT5, AKT and ERK pathways, in FLT3-ITD AML cell lines. In the mouse models with FLT3-ITD and FLT3-ITD-F691L mutation, ningetinib showed superior anti-leukemia activity to existing clinical drugs gilteritinib and quizartinib, significantly prolongating the survival of mice. In addition, ningetinib exhibited activity against patient-derived primary cells harboring FLT3-ITD mutations. CONCLUSION: Overall, our study confirmed the therapeutic role of ningetinib in AML with FLT3-ITD mutations, providing a potential new option for clinically resistant patients.
背景：FMS 样酪氨酸激酶 3 内部串联重复（FLT3-ITD）是急性髓系白血病（AML）的常见突变类型，通常与患者预后不良相关。随着分子诊断技术的进步和酪氨酸激酶抑制剂（TKI）的发展，FLT3-ITD 突变的 AML 患者的总生存期（OS）在一定程度上得到了延长，但复发和耐药仍然是巨大的挑战。奈拉替尼是一种针对与肿瘤发病机制相关的各种激酶的新型 TKI，正在进行肺癌的临床试验。在这项研究中，我们在体内和体外探索了奈拉替尼对具有 FLT3 突变的 AML 的抗肿瘤活性。
方法：在表达各种 FLT3 突变的 AML 细胞系和 Ba/F3 细胞中进行细胞增殖测定，以验证奈拉替尼的体外抗白血病活性。免疫印迹分析用于验证奈拉替尼对 FLT3 蛋白和下游途径的影响。分子对接和 CETSA 用于验证奈拉替尼与靶蛋白的相互作用。在 Ba/F3-FLT3-ITD、MOLM13、Ba/F3-FLT3-ITD-F691L、MOLM13-FLT3-ITD-F691L 诱导的白血病小鼠模型中评估奈拉替尼的体内生存获益。我们还使用患者来源的原代细胞来确定奈拉替尼的疗效。
结果：奈拉替尼抑制细胞增殖，阻断细胞周期，诱导细胞凋亡，并与 FLT3 结合抑制其下游信号通路，包括 STAT5、AKT 和 ERK 通路，在 FLT3-ITD AML 细胞系中。在具有 FLT3-ITD 和 FLT3-ITD-F691L 突变的小鼠模型中，奈拉替尼对现有临床药物吉特替尼和夸扎替尼表现出优越的抗白血病活性，显著延长了小鼠的生存时间。此外，奈拉替尼对携带 FLT3-ITD 突变的患者来源原代细胞具有活性。
结论：总的来说，我们的研究证实了奈拉替尼在具有 FLT3-ITD 突变的 AML 中的治疗作用，为临床耐药患者提供了一种潜在的新选择。
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